DERIVES DE SUBSTITUTION D'AMIDES D'ACIDE QUINOLEINE-2-CARBOXYLIQUE; METHODE DE PREPARATION ET UTILISATION COMME MEDICAMENTS ET INTERMEDIAIRES

SUBSTITUTED QUINOLINE-2-CARBOXYLIC ACID AMIDES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS AND INTERMEDIATE PRODUCTS

Abrégé anglais

Substituted quinoline-2-carboxamides, their preparation
and their use as pharmaceuticals, and intermediates
The invention relates to substituted quinoline-2-
carboxylic acid amides of the formula I
<IMG> (I) ,
their preparation and their use, and intermediates which
are formed in the preparation of the compounds of the
formula I.
The compounds according to the invention are used as
inhibitors of prolyl 4-hydroxylase and as pharmaceuticals
(medicaments) for treatment of fibrotic diseases.

Revendications

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THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the formula (I)
<IMG> (I)
in which
A is (C1-C4)-alkylene, which is optionally substituted
by one or two substituents from the series consist-
ing of halogen, cyano, nitro, trifluoromethyl,
(C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy,
-O-[CH2]X-CfH (2f+1-g) Halg, (C1-C6)-alkylmercapto,
(C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl,
(C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl,
carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-
alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C -3C )8-
cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy,
anilino, N-methylanilino, phenylmercapto,
phenylsulfonyl, phenylsulfinyl, sulfamoyl,
N-(C1-C4)-alkylsulfamoyl and N,N-di-(C1-C4)-
alkylsulfamoyl, or
by (C6-C12)-aryloxy, (C7-C11)-aralkyloxy, (C6-C12)-
aryl or (C7-C11)-aralkyl radical, which carries, in
the aryl part, 1, 2, 3, 4 or 5 identical or
different substituents from the series consisting of
halogen, cyano, nitro, trifluoromethyl, (C1-C6)-
alkyl, (C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Halg,
(C1-C6)-alkylmercapto, (C1-C6)-alkylsulfinyl,
(C1-C6)-alkylsulfonyl, (C1-C6)-alkylcarbonyl,

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(C1-C6)-alkoxycarbonyl, carbamoyl, N-(C1-C4)-
alkylcarbamoyl, N,N-di-(C1-C4)-alkylcarbamoyl,
(C1-C6)-alkylcarbonyloxy, (C3-C8)-cycloalkyl,
sulfamoyl, N-(C1-C4)-alkylsulfamoyl and N,N-di-
(C1-C4)-alkylsulfamoyl, or
by one or more substituents Rx of the .alpha.-C atom of an
.alpha.-amino acid, being a naturally occuring L-amino
acid or a D isomer thereof;
B is an acid grouping from the series comprising
-CO2H, -CONHCOR"', -CONHSOR"', CONHSO2R"', -NHSO2CF3,
tetrazolyl, imidazolyl and 3-hydroxyisoxazolyl, in
which R"' is aryl, heteroaryl, (C3-C7)-cycloalkyl or
(C1-C4)-alkyl, optionally monosubstituted by
(C6-C12)-aryl, heteroaryl, OH, SH, (C1-C4)-alkyl,
(C1-C4)-alkoxy, (C1-C4)-thioalkyl, -sulfinyl or
-sulfonyl, CF3, Cl, Br, F, I, NO2, -COOH, (C2-C5)-
alkoxycarbonyl, NH2, mono- or di-(C1-C4-alkyl)-amino
or (C1-C4)-perfluoroalkyl,
R1, R2, R3, R4 and R5 are identical or different and are
hydrogen, hydroxyl, halogen, cyano, trifluoromethyl,
nitro, carboxyl, (C1-C20)-alkyl, (C3-C8)-cycloalkyl,
(C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cyclo-
alkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-
cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-
(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-
(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy-
(C1-C6)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-
(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-
(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl,
(C7-C16)-aralkenyl, (C7-C16)-aralkynyl, (C2-C20)-
alkenyl, (C2-C20)-alkynyl, (C1-C20)-alkoxy, (C2-C20)-
alkenyloxy, (C2-C20)-alkynyloxy, retinyloxy,
(C1-C20)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-
(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy-
(C1-C8)-alkyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy,
(C6-C12)-aryloxy-(C1-C6)-alkoxy, (C7-C16)-aralkoxy-

- 70 -
(C1-C6)-alkoxy, (C1-C16)-hydroxyalkyl, (C6-C16)-
aryloxy-(C1-C8)-alkyl, (C7-C16)-aralkoxy-(C1-C8)-
alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl,
(C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl,
(C2-C20)-alkenyloxy-(C1-C6)-alkyl, (C2-C20)-
alkynyloxy-(C1-C6)-alkyl, retinyloxy-(C1-C?)-alkyl,
-O-[CH2-]xCfH(2f+1-g)Halg, (C1-C6)-chlorofluoroalkoxy,
(C1-C20)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl,
(C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl,
cinnamoyl, (C2-C20)-alkenylcarbonyl, (C2-C20)-
alkynylcarbonyl,
(C2-C20)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, ( C7 -C16)-
aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl,
(C2-C20)-alkenyloxycarbonyl, retinyloxycarbonyl,
(C2-C20)-alkynyloxycarbonyl, (C6-C12)-aryloxy-
(C1-C6)-alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-
alkoxycarbonyl, (C3-C8)-cycloalkyl-(C -C1)-alkoxy-
carbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxycarbonyl,
(C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-
carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-
aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)-alkenyl-
carbonyloxy, (C2-C12)-alkynylcarbonyloxy,
(C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy (C1-C12)-
alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy,
(C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxy-
carbonyloxy, (C2-C12)-alkenyloxycarbonyloxy,
(C2-C12)-alkynyloxycarbonyloxy,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-
(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-
carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl,
N-(C1-C10)-alkyl-N- (C3-C8) -cycloalkylcarbamoyl,
N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl,
N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-

- 71 -
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl,
N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-
aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C-C6)?6
arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-
aralkylcarbamoyl, N-((C1-C12)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-
alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-
(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-
((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, CON(CH2)h, in which a CH2 group can
be replaced by O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-
cycloalkylimino, N-(C3-C8)-cycloalkyl-(C1-C12)-alkyl-
imino, N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino
or N-(C1-C12)-alkoxy-(C1-C6)-alkylimino and h is 3 to
7, or a carbamoyl radical of the formula J
<IMG>
in which
Rx is the substituent of an L- or D-.alpha.-amino acid,
s is 1, 2, 3, 4 or 5 and
T is OH, OR or NR*R**, in which
R*, R** and R*** are identical or different and are
hydrogen, (C6-C12)-aryl, (C7-C11)-aralkyl,
(C1-C8)-alkyl, (C3-C8)-cycloalkyl, (+)-dehydro-
abietyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-
aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-
(C1-C8)-alkyl, (C1-C10)-alkanoyl, optionally
substituted (C7-C16)-aralkanoyl or optionally

- 72 -
substituted (C6-C12)-aroyl, or
R* and R** together are -[CH2]h, in which one CH2
group can be replaced by O, S, SO, SO2,
N-acylamino, N-(C1-C10)-alkoxycarbonylimino,
N-(C1-C8)-alkylimino, N-(C3-C8)-cyclo-
alkylimino, N-(C3-C8)-cycloalkyl-(C1-C4)
alkylimino, N-(C6-C12)-arylimino, N-(C7-C16)-
aralkylimino or N-(C1-C4)-alkoxy-(C-C1)-6
alkylimino and h is 3 to 7,
or further wherein R1 R2 R3 R4 and R5 are
identical or different and are:
carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-
(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-
carbamoyloxy, N-(C6-C12)-arylcarbamoyloxy,
N-(C7-C16)-aralkylcarbamoyloxy, N-(C ?C ?-alkyl-N-
(C6-C12)-arylcarbamoyloxy, N-(C -C1)-?alkyl-N-
(C7-C16)-aralkylcarbamoyloxy, N-((C1-C10) -
alkyl)carbamoyloxy, N-((C6-C12)-aryloxy-(C1-C10)-
alkyl)carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyloxy, N-(XC1-C10)-alkyl-N-((C1-C10)
alkoxy)-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)-
alkyl-N-((C6-C12)-aryloxy)- (C1-C10)-alkyl)-
carbamoyloxy, N-(C1-C10)-alkyl-N-((C7 -C16) -
aralkyloxy-(C1-C10)-alkyl)carbamoyloxy,
NRYRZ, wherein RY and RZ are independently selected
from (C1-C12)-alkyl, (C ?-C ?-cycloalkyl, (C ?-C 12-
alkenyl, (C3-C12)-alkynyl, (C6-C12)-aryl, (C7-C11)-
aralkyl, (C1-C12)-alkoxy,(C7-C12)-aralkoxy,
(C1-C12)-alkanoyl, (C3-C8)-cycloalkanoyl, (C6-C12)-
aroyl, (C7-C16)-aralkanoyl,
and further wherein RY and RZ together are -[CH2]h-,
wherein one CH2-group can be replaced by O, S, N-
(C1-C4)-alkylcarbonylimino or N-(C1-C4)-
alkoxycarbonylimino, and h is 3 to 6,

- 73 -
(C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8) -
cycloalkanoylamino-(C1-C8)-alkyl, (C6-C12)-
aroylamino-(C1-C8)-alkyl, (C7-C16)-aralkanoylamino-
(C1-C8)-alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)
alkylamino-(C1-C10)-alkyl, N,N-di(C1-C10)-alkyl-
amino-(C1-C10)-alkyl, (C3-C8)-cycloalkylamino-
(C1-C10)-alkyl, (C1-C20)-alkylmercapto, (C1-C20)-
alkylsulfinyl, (C1-C20)-alkylsulfonyl, (C6-C12)-
arylmercapto, (C6-C12)-arylsulfinyl, (C6-C12)-aryl-
sulfonyl, (C7-C16)-aralkylmercapto, (C7-C16)-aralkyl-
sulfinyl, (C7-C16)-aralkylsulfonyl, (C1-C12)-alkyl-
mercapto-(C1-C6)-alkyl, (C1-C12)-alkylsulfinyl-
(C1-C6)-alkyl, (C1-C12)-alkylsulfonyl-(C1-C6)-alkyl,
(C6-C12)-arylmercapto-(C1-C6)-alkyl, (C6-C12)-aryl-
sulfinyl-(Cl-C6)-alkyl, (C6-C12)-arylsulfonyl-
(C1-C6)-alkyl, (C7-C16)-aralkylmercapto-(C1-C6)-
alkyl, (C7-C16)-aralkylsulfinyl-(C1-C6)-alkyl,
(C7-C16)-aralkylsulfonyl-(C1-C6)-alkyl,
sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-
(C1-C10)-alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl,
N-(C6-C12)-arylsulfamoyl, N-(C7-C16)-aralkylsulf-
amoyl, N-(C1-C10)-alkyl-N-(C6-C12)-arylsulfamoyl,
N-(C1-C10)-alkyl-N- (C7-C16) -aralkylsulfamoyl,
(C1-C10)-alkyl-sulfonamido, N-((C1-C10)-alkyl)-
(C1-C10)-alkylsulfonamido, (C7-C16)-aralkyl-
sulfonamido, or N-(C1-C10)-alkyl-(C7-C16)-aralkyl-
sulfonamido,
where the radicals which contain an aryl radical can
in turn be substituted on the aryl by 1 to 5 ident--
ical or different radicals from the series
comprising:
hydroxyl, halogen, cyano, trifluoromethyl, nitro,
carboxyl, (C1-C16)-alkyl, (C3-C8)-cycloalkyl,
(C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-cyclo-
alkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-
cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-
(C1-C12)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkyl-
(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy-

- 74 -
(C1-C6)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-
(C1-C6)-alkyl, (C3-C8)- cycloalkoxy-(C -?)?alkoxy-
(C1-C8)-alkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl,
(C2-C16)-alkenyl, (C2-C12)-alkynyl, (C1-C16)-alkoxy,
(C1-C16)-alkenyloxy, (C1-C12)-alkoxy-(C1-C12)-alkyl,
(C1-C12)-alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-
(C1-C8)-alkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy,
(C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy,
(C7-C16)-aralkoxy- (C1-C6)-alkoxy (C1-C8) -
hydroxyalkyl, (C6-C16)-aryloxy-(C1-C8)-alkyl,
(C7-C16)-aralkoxy-(C1-C8)-alkyl, (C6-C12)-aryloxy-
(C1-C8)-alkoxy-(C1-C6)-alkyl, (C7-C12)-aralkyloxy-
(C1-C8)-alkoxy-(C1-C6)-alkyl, -O-[CH2-]xCfH(2f+1-g) Fg,
-OCF2Cl, -OCF2-CHFCl,
(C1-C12)-alkylcarbonyl, (C3-C?-cycloalkylcarbonyl,
(C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl,
(C1-C12)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-
aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl,
(C2-C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxy-
carbonyl, (C6-C12)-aryloxy-(C1-C6)-alkoxycarbonyl,
(C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-C8)-
cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cyclo-
alkoxy-(C1-C6)-alkoxycarbonyl,
(C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-
carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-
aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)-alkenyl-
carbonyloxy, (C2-C12)-alkynylcarbonyloxy,
(C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkoxy (C1-C12)-
alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy,
(C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxy-
carbonyloxy, (C2-C12)-alkenyloxycarbonyloxy,
(C2-C12)-alkynyloxycarbonyloxy,

- 75 -
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-
(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-
carbamoyl, N,N-dicyclo-(C3-C8)-alkylcarbamoyl,
N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl,
N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl,
N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl,
N-(C6-C12)-arylcarbamoyl, N- (C7-C16 ) -aralkyl-
carbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-arylcarbamoyl,
N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl,
N ((C1-C16)-alkoxy-(C1-C10)-alkyl)carbamoyl,
N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl,
N-((C7-C16) -aralkyloxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-
aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-
((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl,
CON(CH2)h, in which one CH2 group can be replaced by
O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkyl-
imino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino,
N-(C6-C12)-arylimino, N-(C -? ?aralkylimino or
N-(C1-C4)-alkoxy-(C1-C6)-alkylimino and h is 3 to 7,
carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-
(C1-C12)-alkylcarbamoyloxy, N-(C3-C8) -cycloalkyl-
carbamoyloxy, N-(C6-C16)-arylcarbamoyloxy,
N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-
(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-
(C7-C16)-aralkylcarbamoyloxy, N-((C1-C10)-
alkyl)carbamoyloxy, N-((C6-C12)-aryloxy-(C1-C10)-
alkyl)carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyloxy, N-(C1-C10)-alkyl-N-((C1-C10)-
alkoxy-(C1-C10)-alkyl)carbamoyloxy, N-(C1-C10)
alkyl-N-((C6-C12)-aryloxy-(C1-C10)-alkyl)carba-
moyloxy, N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-
(C1-C10)-alkyl)carbamoyloxy,

- 76 -
amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino,
(C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino,
(C3-C12)-alkynylamino, N-(C6-C12)-arylamino,
N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino,
N-alkyl-arylamino, (C1-C12)-alkoxyamino, (C IC ?-
alkoxy-N-(C1-C10)-alkylamino,
(C1-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino,
(C6-C12)-aroylamino, (C7-Cl6)-aralkanoylamino,
(C1-C12)-alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-
cycloalkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-
N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-
alkylamino,
(C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cyclo-
alkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroylamino-
(C1-C8)-alkyl, ( C7-Cl6) -aralkanoylamino-(C1-C8)-
alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-
(C1-C10)-alkyl, N,N-di-(C1-C10)-alkylamino-(C1-C10)-
alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl,
(C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl,
(C1-C12)-alkylsulfonyl, (C6-C16)-arylmercapto,
(C6-C16)-arylsulfinyl, (C6-C16)-arylsulfonyl,
(C7-C16)-aralkylmercapto, (C7-C16)-aralkylsulfinyl
and (C7-C16)-aralkylsulfonyl, or optionally carries
up to 3 of said radical substituents for said aryl
and two adjacent carbon atoms of an arylalkoxy,
radical recited in the definition of R1-R5 together
carry a chain -[CH2]- and/or -CH=CH-CH=CH, where one
CH2 group of the chain is optionally replaced by O,
S, SO, SO2 or NR',
R1 and R2, R2 and R3, R3 and R4, or R4 and R5 form a chain
[CH2]o, in which one or two CH2 groups of the chain,
which is saturated or unsaturated with a C=C double
bond, are optionally replaced by O, S, SO, SO2 or
NR', in which o is 3, 4 or 5, and

- 77 -
R" is hydrogen, (C6-C12)-aryl, (C1-C8)-alkyl, (C1-C8)-
alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-C8)-
alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-
alkanoyl, optionally substituted (C7-C16)-aralkanoyl
or optionally substituted (C6-C12)-aroyl, and
m is 0 or 1,
f is 1 to 8,
g is 0 or 1 to (2f + 1),
x is 0 to 3 and
h is 3 to 6, or a physiologically active salt thereof.
2. A compound of the formula I as claimed in claim 1,
in which
A is (C1-C3)-alkylene, which is optionally mono-
substituted by halogen, cyano, trifluoromethyl,
(C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy
or -O-[CH2]x-CfH(2f+1-g)Fg or
A is -CHRX-, in which Rx is one of the substituents of
the .alpha.-C atom of an .alpha.-amino acid, in particular of a
naturally occuring L-amino acid or its D isomer,
B is -CO2H,
R1 and R5 are identical or different and are hydrogen,
(C1-C12)-alkyl, (C1-C12)-alkenyl, chlorine, fluorine,
bromine, trifluoromethyl, (C1-C12)-alkylsulfonyl,
(C1-C12)-alkylsulfinyl, phenylsulfonyl or phenyl-
sulfinyl; where phenyl is optionally substituted by
fluorine, chlorine or (C1-C5)-alkoxy, (C1-C10)-
alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, (C1-C6)-alkoxy-
(C1-C6)-alkoxy or (C3-C8)-cycloalkoxy,
R2, R3 and R4 are identical or different and are hydro-
gen, hydroxyl, (C1-C20)-alkyl, (C2-C20)-alkenyl,
(C2-C20)-alkynyl, (C1-C20)-alkoxy, (C2-C20)-alkenyl-
oxy, (C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-

- 78 -
alkoxy-(C1-C8)-alkyl, (C2-C20)-alkenyloxy-(c -?)8
alkyl, retinyloxy-(C1-C6)-alkyl, (C2-C20)-alkynyloxy-
(C1-C8)-alkyl, halogen, cyano, trifluoromethyl,
(C1-C12)-hydroxyalkyl, (C1-C20)-alkanoyl, (C7-C16) -
aralkanoyl, (C6-C12)-aroyl, (C6-C12)-aryl, (C7-C16)
aralkyl, -O-[CH2]x-CfH(2f+1-g)Fg, (C1-C18)-alkyl-
mercapto, (C1-C18)-alkylsulfinyl, (C1-C18)-alkyl-
sulfonyl, (C6-C12)-arylmercapto, (C6-C12)-aryl-
sulfinyl), (C6-C12)-arylsulfonyl, (C7-C12)-aralkyl-
mercapto, (C7-C12)-aralkylsulfinyl, (C7-C12)-aralkyl-
sulfonyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy,
carboxyl, (C1-C20)-alkoxycarbonyl, (C -? )12alkoxy-
(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl,
(C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxy-
carbonyl, (C2-C2? -alkenyloxycarbonyl, retinyloxy-
carbonyl, (C2-C20)-alkynyloxycarbonyl, (C3-C8)-cyclo-
alkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-
(C1-C6)-alkoxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-
alkoxycarbonyl, (C7-C16) -aralkoxy-(C -C1)-6
alkoxycarbonyl,
(C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C )-?alkoxy-
(C1-C12)-alkoxy, (C1-Cl2)-alkoxy-(C -C1)-?alkoxy-
(C1-C6)-alkyl, (C7-C11)-aralkyloxy, (C3-C8)-cyclo-
alkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-
cycloalkyloxy, (C3-C8)-cycloalkyl-(C -C1 )-?alkoxy,
(C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cyclo-
alkyloxy-(C1-C8)-alkoxy, (C3-C8)-cycloalkyl-(C1-C12)-
alkyl-(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C6)-
alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C6)-
alkoxy-(C1-C6)-alkyl, NRYRZ, substituted (C6-C12)-
aryloxy-(C1-C6)-alkyl, (C7-C11)-aralkoxy-(C1-C6)-
alkyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl,
(C7-C11)-aralkyloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl,
(C6-C12)-aryloxy-(C1-C6)-alkoxy or (C7-C11)-aralkoxy-
(C1-C6)-alkoxy,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-
(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-

- 79 -
carbamoyl, N,N-dicyclo(C3-C8)-alkylcarbamoyl,
N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl,
N-(C3-C8)-cycloalkyl-(C1-C16)-alkyl)carbamoyl,
N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl,
N-(C6-C12)-arylcarbamoyl, N- (C7 -C16 ) -
aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-
arylcarbamoyl, N-(C1-C10)-alkyl-N- (C7 -C16 ) -
aralkylcarbamoyl, N-((C1-C12)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)
alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C ?C )6-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-
alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-
((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, or CON(CH2)h, in which one CH2
group can be replaced by O, S, N-(C1-C16)-alkyl-
imino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cyclo-
alkyl-(C1-C12)-alkylimino, N-(C6-C12)-arylimino,
N-(C7-C16)-aralkylimino or N-(C1-C12)-alkoxy-(C1-C6)-
alkylimino and h is 3 to 7, where an aromatic rad-
ical carries 1, 2, 3, 4 or 5 identical or different
substituents from the series comprising of hydrogen,
halogen, cyano, nitro, hydroxyl, trifluoromethyl,
(C1-C16)-alkyl, (C2-C16)-alkenyl, (C1-C6)-hydroxy-
alkyl, (C1-C16)-alkoxy, (C1-C16)-alkenyloxy, -O-
[CH2]xCfH(2f+1-g)Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-
alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkyl-
sulfonyl, (C1-C6)-alkylcarbonyl, (C -?)?-alkoxy-
carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-
di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy,
(C3-C8)-cycloalkylcarbamoyl, phenyl, benzyl,
phenoxy, benzyloxy, phenylmercapto, phenylsulfonyl,
phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl
and N,N-di-(C1-C4)-alkylsulfamoyl, or optionally
carries up to 3 of the abovementioned identical or
different substituents and two adjacent carbon atoms
of the aralkyloxy radical recited in the definition

- 80 -
of R1-R5 together carry a chain -[CH2]- and/or -
CH=CH-CH=CH-, where one CH2 group of the chain is
optionally replaced by O, S, SO, SO2 or NR',
RY and RZ are identical or different and are hydrogen,
(C6-C12)-aryl, (C1-C10)-alkyl, (C3-C10)-cycloalkyl,
(C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy (C1-
C8)-alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-
alkanoyl, optionally substituted (C7-C16)-
aralkanoyl, or optionally substituted (C6-C12)-
aroyl, or
RY and RZ together are -[CH2]h-, wherein one CH group can
be replaced by O, S, N-(C1-C4)-alkanoylimino or
N-(C1-C4)-alkoxycarbonylimino,
m is 0 or 1,
f is 1 to 8,
g is 0 or 1 to (2f + 1),
h is 3 to 6 and
x is 0 to 3, or a physiologically active salt thereof.
3. A compound of the formula I as claimed in claims 1
or 2, in which
m is 0,
A is a -CH2- group, which can be substituted by a
methyl group,
B is -CO2H,
R1 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, chlorine
or bromine,
R5 is hydrogen, fluorine, chlorine or methyl and
R2, R3 and R4 are identical or different and are hydro-
gen, (C1-C18)-alkyl, (C2-C18)-alkenyl, (C2-C18)-
alkynyl, phenyl, chlorine, fluorine, bromine,
hydroxyl, trifluoromethyl, (C1-C18)-alkylsulfinyl,
(C1-C18)-alkylsulfonyl, phenylsulfinyl, phenyl-
sulfonyl, naphthylsulfinyl, naphthylsulfonyl,
(C1-C18)-alkoxy, (C3-C8)-cycloalkoxy, (C1-C8)-alkoxy-

- 81 -
(C1-C8)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, phenyl-
(C1-C4)-alkoxy, phenoxy, (C1-C12)-alkanoyl, phenyl-
(C1-C4)-alkanoyl or benzoyl, where, in substituents
with a phenyl or naphthyl ring, this optionally
carries up to 5 identical or different substituents
from the series comprising fluorine, chlorine,
bromine, nitrile, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -o-[CH2]x-CfH(2f+l-g)Fg or (C1-C6)-
alkylsulfonyl,
or a physiologically active salt thereof.
4. A compound of the formula I as claimed in claims 1
to 3, in which
m is 0,
A is a -CH2- group,
B is -CO2H,
R1 and R5 are hydrogen and
R2, R3 and R4 are identical or different and are hydro-
gen, (C1-C18)-alkyl, (C1-C18)-alkenyl, phenyl, chlor-
ine, fluorine, bromine, trifluoromethyl, (C1-C18)-
alkylsulfinyl, (C1-C18)-alkylsulfonyl, phenyl-
sulfinyl, phenylsulfonyl, naphthylsulfinyl,
naphthylsulfonyl, (Cl-C18)-alkoxy, (C3-C8)-cyClo-
alkoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy, -O-[CH2]x-
CfH(2f+l-g)Fg, phenyl-(C1-C4)-alkoxy, phenoxy,
(C1-C12)-alkanoyl, phenyl-(C1-C4)-alkanoyl or
benzoyl, where, in substituents having a phenyl or
naphthyl ring, this optionally carries up to 5
identical or different substituents from the series
comprising fluorine, chlorine, bromine, nitrile,
trifluoromethyl, (C1-C )?alkyl, (C -? )?alkoxy,
-O-[CH2]x-CfH(2f+1-g)Fg and (C1-C6)-alkylsulfonyl, or
a physiologically active salt thereof.
5. A compound of the formula I as claimed in claims 1
to 4, in which
m is 0,
A is a -CH2- group,
R1 and R5 are hydrogen,

- 82 -
one of the substituents R2, R3 or R4 is hydrogen and the
other two are identical or different and are hydrogen,
(C1-C16)-alkyl, fluorine, chlorine, bromine, trifluoro-
methyl, (C1-C16)-alkylsulfonyl, phenylsulfonyl, (C1-C16)-
alkoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy, -O-[CH2]x-
CfH(2f+1g)Fg, benzyloxy or phenoxy, where, in substituents
which contain a phenyl ring, this optionally carries up
to 3 substituents from the series comprising fluorine,
chlorine, bromine, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -O-[CH2]X-C ? (2f+1-g? g or (C-?C )4-alkyl-
sulfonyl, or a physiologically active salt thereof.
6. A compound of the formula I as claimed in claims 1
to 5, in which
m is 0,
A is a -CH2- group,
R1, R2 and R5 are hydrogen and
R3 and R4 are identical or different and are hydrogen,
(C1-C16)-alkyl, fluorine, chlorine, trifluoromethyl,
(C1-C16)-alkylsulfonyl, phenylsulfonyl, naphthylsulfonyl,
(C1-C16)-alkoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy, -O-[CH2]x-
CfH(2f+1-g)Fg, benzyloxy or phenoxy, where, in substituents
which contain a phenyl ring, this optionally carries up
to 3 substituents from the series comprising fluorine,
chlorine, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,
-O-[CH2]x-CfH(2f+1-g)Fg and (C1-C4)-alkylsulfonyl, or a
physiologically active salt thereof.
7. A compound of the formula I as claimed in claims 1
to 6, in which
m is 0,
A is a -CH2- group,
R1, R2, R3 and R5 are hydrogen and
R4 is hydrogen, (C1-C12)-alkyl, fluorine, chlorine,
bromine, trifluoromethyl, (C1-C12)-alkylsulfonyl, phenyl-
sulfonyl, naphthylsulfonyl, (C1-C12)-alkoxy, (C1 -C6)-
alkoxy-(C1-C6)-alkoxy, -O-[CH2]X-CfH(2f+1-g)Fg, benzyloxy or
phenoxy, where, in substituents which contain a phenyl or
naphthyl ring, this is optionally monosubstituted by

- 83 -
fluorine, chlorine, bromine, trifluoromethyl, (C1-C6)-
alkyl, (C1-C6)-alkoxy, -O-[CH2]X-CfH(2f+1-g)Fg or (C1-C4)-
alkylsulfonyl, or a physiologically active salt thereof.
8. A compound of the formula I as claimed in claims 1
to 6, in which
m is 0,
A is a -CH2- group,
R1, R3, R4 and R5 are hydrogen and
R2 is hydrogen, (C1-C12)-alkyl, fluorine, chlorine,
bromine, trifluoromethyl, (C1-C12)-alkylsulfonyl, phenyl-
sulfonyl, naphthylsulfonyl, (C1-C12)-alkoxy, (C1-C6)-
alkoxy-(C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, benzyloxy or
phenoxy, where, in substituents which contain a phenyl or
naphthyl ring, this is optionally monosubstituted by
fluorine, chlorine, bromine, trifluoromethyl, (C1-C6)-
alkyl, (C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg or (C1-C4)-
alkylsulfonyl, or a physiologically active salt thereof.
9. A compound of the formula I as claimed in claims 1
to 6, in which
m is 0,
A is a -CH2- group,
R1, R2 and R5 are hydrogen,
R4 is hydrogen or chlorine and
R3 is hydrogen, fluorine, chlorine, (C1-C12)-alkoxy,
(C1-C4)-alkoxy-(C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg,
phenylsulfonyl, naphthylsulfonyl or phenoxy, where, in
substituents which contain a phenyl or naphthyl ring,
this optionally carries up to 3 identical or different
substituents, preferably one substituent, from the series
comprising fluorine, chlorine, bromine, trifluoromethyl,
trifluoromethoxy, (C1-C6)-alkyl and (C1-C6)-alkoxy, or a
physiologically active salt thereof.
10. A compound of the formula I as claimed in claims 1
to 6 and 9, in which
m is 0,
A is a -CH2- group,

- 84 -
R1, R2, R4 and R5 are hydrogen and
R3 is hydrogen, fluorine, chlorine, (C1-C12)-alkoxy,
(C1-C4)-alkoxy-(C1-C6)-alkoxy, -O-[CH2]y-CfH(2f+1-g)Fg,
phenylsulfonyl, naphthylsulfonyl or phenoxy, where, in
substituents which contain a phenyl or naphthyl ring,
this optionally carries up to 3 identical or different
substituents, preferably one substituent, from the series
consisting of fluorine, chlorine, bromine, trifluoro-
methyl, trifluoromethoxy, (C1-C6)-alkyl and (C1-C6)-
alkoxy, or a physiologically active salt thereof.
11. A compound of the formula I as claimed in claims 1
and 2, in which
A is (C1-C3)-alkylene, which is optionally mono-
substituted by halogen, cyano, trifluoromethyl,
(C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy
or -O-[CH2]x-CfH(2f+1-g)Fg or
A is -CHRx-, in which Rx is one of the substituents of
the .alpha.-C atom of an .alpha.-amino acid, in particular of a
naturally occuring L-amino acid or its D isomer,
B is -CO2H,
R1 and R5 are identical or different and are hydrogen,
(C1-C12)-alkyl, (C2-C12)-alkenyl, chlorine, fluorine,
bromine, trifluoromethyl, (C1-C12)-alkylsulfonyl,
(C1-C12)-alkylsulfinyl, phenylsulfonyl or phenyl-
sulfinyl; where phenyl is optionally substituted by
fluorine, chlorine or (C1-C5) -alkoxy, (C1-C10)-
alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, (C1-C6)-alkoxy-
(C1-C6)-alkoxy or (C3-C8)-cycloalkoxy,
R2 is hydroxyl, (C1-C20)-alkyl, (C2-C20)-alkenyl,
(C2-C20)-alkynyl, (C1-C20)-alkoxy, (C2-C20)-alkenyl-
oxy, (C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-
alkoxy-(C1-C8)-alkyl, (C2-C20)-alkenyloxy-(C1-C8)-
alkyl, retinyloxy-(C1-C6)-alkyl, (C2-C20)-alkynyloxy-

- 85 -
(C1-C8)-alkyl, halogen, cyano, trifluoromethyl,
(C1-C12)-hydroxyalkyl, (C ?C 2)-alkanoyl, (C ?C 1?-
aralkanoyl, (C6-C12)-aroyl, (C6-C12)-aryl, (C7-C16)-
aralkyl, -O-[CH2]x-CfH(2f+1-g)Fg, (C1-C18)-alkyl-
mercapto, (C1-C18)-alkylsulfinyl, (C1-C18)-alkyl-
sulfonyl, (C6-C12)-arylmercapto, (C -C6 )-aryl-
sulfinyl, (C6-C12)-arylsulfonyl, (C7-C12)-aralkyl-
mercapto, (C7-C12)-aralkylsulfinyl, (C7-C12)-aralkyl-
sulfonyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy,
carboxyl, (C1-C20)-alkoxycarbonyl, (C1-C12)-alkoxy-
(C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl,
(C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxy-
carbonyl, (C2-C20)-alkenyloxycarbonyl, retinyloxy-
carbonyl, (C2-C20)-alkynyloxycarbonyl, (C3-C8)-cyclo-
alkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-
(C1-C6)-alkoxycarbonyl, (C6-C )-?ryloxy-(C -C1)-6
alkoxycarbonyl, (C7 -C16)-aralkoxy-(C1-C6)-
alkoxycarbonyl,
(C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-
(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy-
(C1-C6)-alkyl, (C7-C11)-aralkyloxy, (C3-C8)-cyclo-
alkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-
cycloalkyloxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy,
(C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cyclo-
alkyloxy-(C1-C8)-alkoxy, (C3-C8)-cycloalkyl-(C1-C12)-
alkyl-(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C6)-
alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C6)-
alkoxy-(C1-C6)-alkyl, NRYRZ, substituted (C -?C ?-
aryloxy-(C1-C6)-alkyl, (C7-C11)-aralkoxy-(C1-C6)-
alkyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl,
(C7-C11)-aralkyloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl,
(C6-C12)-aryloxy-(C1-C6)-alkoxy or (C7-C11)-aralkoxy-
(C1-C6)-alkoxy,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-
(C1-C12)-alkylcarbamoyl, N-(C3-C ) -?ycloalkyl-
carbamoyl, N,N-dicyclo(C3-C8)-alkylcarbamoyl,
N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl,

- 86 -
N-(C3-C8)-cycloalkyl-(C1-C16)-alkyl)carbamoyl,
N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl,
N-(C6-C12)-arylcarbamoyl, N- (C7-C16) -aralkyl-
carbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-arylcarbamoyl,
N-(C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl,
N-((C1-C12)-alkoxy-(C1-C10)-alkyl)carbamamoyl,
N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamamoyl,
N-((C7-C16)-aralkyloxy-(C1-C6)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C6-C12)-
aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-
N-((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, or
CON(CH2)h, in which one CH2 group can be replaced by
O, S, N-(C1-C16)-alkylimino, N-(C3-C8)-cycloalkyl-
imino, N-(C3-C8)-cycloalkyl-(C1-C12)-alkylimino,
N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or
N-(C1-C12)-alkoxy-(C1-C6)-alkylimino and h is 3 to 7,
where an aromatic radical carries 1, 2, 3, 4 or 5
identical or different substituents from the series
comprising hydrogen, halogen, cyano, nitro,
hydroxyl, trifluoromethyl, (C1-C16)-alkyl, (C2-C16)-
alkenyl, (C1-C6)-hydroxyalkyl, (C1-C16)-alkoxy,
(C1-C16)-alkenyloxy, -O-[CH2]XCfH(2f+1-g) Fg, -OCF2Cl,
-O-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-
alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C -C1)-6
alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-
(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-
alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-
cycloalkylcarbamoyl, phenyl, benzyl, phenoxy,
benzyloxy, phenylmercapto, phenylsulfonyl,
phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl
and N,N-di-(C1-C4)-alkylsulfamoyl, or optionally
carries up to 3 of the abovementioned identical or
different substituents and two adjacent carbon atoms
of the aralkyloxy radical together carry a chain
-[CH2]- and/or -CH=CH-CH=CH-, where one CH2 group of

- 87 -
the chain is optionally replaced by O, S, SO, SO2 or
NR',
R3 is hydroxyl, (C1-C20)-alkyl, (C2-C20)-alkenyl,
(C2-C20)-alkynyl, (C11-C20)-alkoxy, (C7-C20)-alkenyl-
oxy, (C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-
alkoxy-(C1-C8)-alkyl, (C2-C20)-alkenyloxy-(C1-C8)-
alkyl, retinyloxy-(C1-C6)-alkyl-(C2-C20)-alkynyloxy-
(C1-C8)-alkyl, fluorine, cyano, trifluoromethyl,
(C1-C12)-hydroxyalkyl, (C1-C20)-alkanoyl, (C7-C16)-
aralkanoyl, (C6-C12)-aroyl, (C6-C12)-aryl, (C7-C16)-
aralkyl, (C1-C18)-alkylmercapto, (C1-C18)-alkyl-
sulfinyl, (C1-C18)-alkylsulfonyl, (C6-C12)-aryl-
mercapto, (C6-C12)-arylsulfinyl, (C7-C12)-aralkyl-
mercapto, (C7-C12)-aralkylsulfinyl, (C7-C12)-aralkyl-
sulfonyl, (C6-C12)-aryloxy, (C7-C16)-aralkyloxy,
apart from benzyloxy, carboxyl, (C1-C20)-alkoxy-
carbonyl, (C1-C12)-alkoxy-(C1-C12)-alkoxycarbonyl,
(C6-C12)-aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl,
(C3-C8)-cycloalkoxycarbonyl, (C2-C20)-
alkenyloxycarbonyl, retinyloxycarbonyl, (C2-C20)-
alkynyloxycarbonyl, (C3-C8) -cycloalkyl-(C1-C6)-
alkyloxycarbonyl, (C3-C8)-cycloalkoxy- (C1-C6)-
alkoxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-
alkoxycarbonyl, (C7-C16) -aralkoxy-(C1-C6)-
alkoxycarbonyl,
-O-[CH2]x-CfH(2f+1-g)Halg apart from trifluoroethoxy,
pentafluoropropoxy and heptafluorobutoxy, (C1-C12)-
alkoxy-(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-
alkoxy-(C1-C6)-alkyl, (C7-C11)-aralkyloxy, (C3-C8)-
cycloalkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl,
(C3-C8)-cycloalkyloxy, (C3-C8)-cycloalkyl-(C1-C )?
alkoxy, (C3-C8)-cycloalkyloxy-(C1-C12)-alkyl,
(C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy, (C3-C8)-cyclo-
alkyl-(C1-C12)-alkyl-(C1-C6)-alkoxy, (C3-C8)-cyclo-
alkyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C8)-
cycloalkoxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, NRYRZ,
substituted (C6-C12)-aryloxy-(C1-C6)-alkyl, (C7-C11)-

- 88 -
aralkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C1-C6)
alkoxy-(C1-C6)-alkyl, (C7-C11)-aralkyloxy-(C1-C6)-
alkoxy-(C1-C6)-alkyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy
or (C7-C11)-aralkoxy-(C1-C6)-alkoxy,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-
(C1-C12)-alkylcarbamoyl, N-(C3-C8) -cycloalkyl-
carbamoyl, N,N-dicyclo(C3-C8)-alkylcarbamoyl,
N-(C1-C10)-alkyl-N-(C3-C8) -cycloalkylcarbamoyl,
N-(C3-C8)-cycloalkyl-(C1-C16)-alkyl)carbamoyl,
N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl,
N-(C6-C12)-arylcarbamoyl, N- (C7 -C16)-
aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-
arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-
aralkylcarbamoyl, N-((C1-C12)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)
alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C6)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-
alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-
((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyl, or CON(CH2)h, in which one CH2
group can be replaced by O, S, N-(C1-C16)-alkyl-
imino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-cyclo-
alkyl-(C1-C12)-alkylimino, N-(C6-C12)-arylimino,
N-(C7-C16)-aralkylimino or N-(C1-C12)-alkoxy-(C1-C6)-
alkylimino and h is 3 to 7, where an aromatic rad-
ical carries 1, 2, 3, 4 or 5 identical or different
substituents from the series comprising hydrogen,
halogen, cyano, nitro, hydroxyl, trifluoromethyl,
(C1-C16)-alkyl, (C2-C16)-alkenyl, (C1-C6)-hydroxy-
alkyl, (C1-C16)-alkoxy, (C1-C16)-alkenyloxy, -O-
[CH2]xCfH (2f+1-g) Fg, -OCF2Cl, -O-CF2-CHFCl, (C1-C6)-
alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkyl-
sulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxy-
carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-
di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy,

- 89 -
(C3-C8)-cycloalkylcarbamoyl, phenyl, benzyl,
phenoxy, benzyloxy, phenylmercapto, phenylsulfonyl,
phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl
and N,N-di-(C1-C4)-alkylsulfamoyl, or optionally
carries up to 3 of the abovementioned identical or
different substituents and two adjacent carbon atoms
of the aralkyloxy radical together carry a chain
-[CH2]- and/or -CH=CH-CH=CH-, where one CH2 group of
the chain is optionally replaced by O, S, SO, SO2 or
NR', and
R4 is hydroxyl, (C1-C20)-alkyl, (C2-C20)-alkenyl,
(C2-C20)-alkynyl, (C1-C20)-alkoxy apart from
1-butoxy, (C2-C20)-alkenyloxy, (C 2-C 20) -alkynyloxy,
retinyloxy, (C1-C20)-alkoxy-(C 1-C 8)-alkyl, (C 2-C 20) -
alkenyloxy-(C1-C8)-alkyl, retinyloxy-(C1-C6)-alkyl,
(C2-C20)-alkynyloxy-(C1-C8)-alkyl, halogen, cyano,
trifluoromethyl, (C1-C12)-hydroxyalkyl, (C1-C20)-
alkanoyl,(C7-C16)-aralkanoyl, (C6-C12)-aroyl,
(C6-C12)-aryl, (C7-C16)-aralkyl, -o-[CH2]x-
CfH(2f+l-g)Fg, (C1-C18)-alkylmercapto, (C1-C18)-alkyl-
sulfinyl, (C1-C18)-alkylsulfonyl, (C6-C12)-aryl-
mercapto, (C6-C )?arylsulfinyl, (C -C )6-aryl-
sulfonyl, (C7-C12)-aralkylmercapto, (C7-C12)-aralkyl-
sulfinyl, (C7-C12)-aralkylsulfonyl, (C6-C12)-aryloxy,
(C7-C16)-aralkyloxy apart from benzyloxy, carboxyl,
(C1-C20)-alkoxycarbonyl, (C1-C12)-alkoxy-(C1-C12)-
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-C16)-
aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl,
(C2-C20)-alkenyloxycarbonyl, retinyloxycarbonyl,
(C2-C20)-alkynyloxycarbonyl, (C3-C8)-cycloalkyl-
(C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy- (C1-C6)-
alkoxycarbonyl, (C6-C12)-aryloxy-(C1-C6)-
alkoxycarbonyl, (C7-C16)-aralkoxy-(C1-C6)-
alkoxycarbonyl,
(C1-C12)-alkoxy-(C1-C12)-alkyl, (C1-C12)-alkoxy-
(C1-C12)-alkoxy, (C1-C12)-alkoxy-(C1-C12)-alkoxy-
(C1-C6)-alkyl, (C7-C11)-aralkyloxy, (C3-C8)-cyclo-

- 90 -
alkyl, (C3-C8)-cycloalkyl-(C1-C12)-alkyl, (C3-C8)-
cycloalkyloxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy,
(C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cyclo-
alkyloxy-(C1-C8)-alkoxy, (C3-C8)-cycloalkyl-(C1-C12)-
alkyl-(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C6)-
alkoxy-(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-?)-?
alkoxy-(C1-C6)-alkyl, NRYRZ, substituted (C6-C12)-
aryloxy-(C1-C6)-alkyl, (C7-C11)-aralkoxy-(C1-C6)
alkyl, (C6-C12)-aryloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl,
(C7-C11)-aralkyloxy-(C1-C6)-alkoxy-(C1-C6)-alkyl,
(C6-C12)-aryloxy-(C1-C6)-alkoxy or (C7-C11)-
aralkyloxy-(C1-C6)-alkoxy,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-
(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-
carbamoyl, N,N-dicyclo(C3-C8)-alkylcarbamoyl,
N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl,
N-(C3-C8)-cycloalkyl-(C1-C16)-alkyl)carbamoyl,
N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl,
N-(C6-C12)-arylcarbamoyl, N- (C7 -C16 ) -
aralkylcarbamoyl, N-(C1-C10)-alkyl-N-(C6-C16)-
arylcarbamoyl, N-(C1-C10)-alkyl-N-(C7-C16)-
aralkylcarbamoyl, N-((C1-C12)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-((C6-C16)-aryloxy-(C1-C10)-
alkyl)carbamoyl, N-((C7-C16)-aralkyloxy-(C1-C6)-
alkyl)carbamoyl, N-(C1-C10)-alkyl-N-((C1-C10)-
alkoxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-
((C6-C12)-aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-
C10)-alkyl-N-((C7 -C16) -aralkyloxy-(C1-C10)-
alkyl)carbamoyl, or CON(CH2)h, in which one CH2
group can be replaced by O, S, N-(C1-C16)-
alkylimino, N-(C3-C8)-cycloalkylimino, N-(C3-C8)-
cycloalkyl-(C1-C12)-alkylimino, N-(C6-C12)-arylimino,
N-(C7-C16)-aralkylimino or N-(C1-C12)-alkoxy-(C1-C6)-
alkylimino and h is 3 to 7, where an aromatic rad-
ical carries 1, 2, 3, 4 or 5 identical or different
substituents from the series comprising hydrogen,

- 91 -
halogen, cyano, nitro, hydroxyl, trifluoromethyl,
(C1-C16)-alkyl, (C2-C16)-alkenyl, (C1-C6)-hydroxy-
alkyl, (C1-C16)-alkoxy, (C1-C16)-alkenyloxy, -O-
[CH2]xCfH(2f+1-g)Fg, -O-CF2Cl, -OCF2-CHFCl, (C1-C6)-
alkylmercapto, (C1-C6)-alkylsulfinyl, (C1-C6)-alkyl-
sulfonyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxy-
carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, N,N-
di-(C1-C4)-alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy,
(C3-C8)-cycloalkylcarbamoyl, phenyl, benzyl,
phenoxy, benzyloxy, phenylmercapto, phenylsulfonyl,
phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl
and N,N-di-(C1-C4)-alkylsulfamoyl, or optionally
carries up to 3 of the abovementioned identical or
different substituents and two adjacent carbon atoms
of the aralkyloxy radical together carry a chain
-[CH2]- and/or -CH=CH-CH=CH-, where one CH2 group of
the chain is optionally replaced by O, S, SO, SO2 or
NR',
RY and RZ are identical or different and are hydrogen,
(C6-C12)-aryl, (C1-C10)-alkyl, (C3-C10)-cycloalkyl,
(C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy (C1-
C8) alkyl, (C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-
alkanoyl, optionally substituted (C7-C16)-
aralkanoyl, or optionally substituted (C6-C12)-
aroyl, or
RY and RZ together are -[CH2]h-, wherein one CH2 group can
be replaced by O, S, N-(C1-C4)-alkanoylimino or
N-(C1-C4)-alkoxycarbonylimino,
m is 0 or 1,
f is 1 to 8,
g is 0 or 1 to (2f + 1),
h is 3 to 6 and
x is 0 to 3, or a physiologically active salt thereof.
12. A compound of the formula I as claimed in claims 3
and 11, in which

- 92 -
m is O,
A is a -CH2- group, which can be substituted by a
methyl group,
B is -CO2H,
R1 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, chlorine
or bromine,
R5 is hydrogen, fluorine, chlorine or methyl,
R2 is (C1-C18)-alkyl, (C2-C18)-alkenyl, (C2-C18)-
alkenyloxy, (C2-C18)-alkynyl, phenyl, chlorine,
fluorine, bromine, hydroxyl, trifluoromethyl,
(C1-C18)-alkylsulfinyl, (C1-C18)-alkylsulfonyl,
phenylsulfinyl, phenylsulfonyl, naphthylsulfinyl,
naphthylsulfonyl, (C1-C18)-alkoxy, (C3-C8)-
cycloalkoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy,
-O-[CH2]x-CfH(2f+1-g)Fg, phenyl-(C1-C4)-alkoxy,
phenoxy, (C1-C12)-alkanoyl, phenyl-(C1-C4)-alkanoyl
or benzoyl, where, in substituents with a phenyl or
naphthyl ring, this optionally carries up to 5
identical or different substituents from the series
comprising fluorine, chlorine, bromine, nitrile,
trifluoromethyl, (C1-C6) -alkyl, (C1-C6) -alkoxy,
-O-[CH2]x-CfH(2f+1-g)Fg or (C1-C6)-alkylsulfonyl, and
R3 is (C1-C18)-alkyl, (C -? )?alkenyl, (C -? ?
alkenyloxy, (C2-C18)-alkynyl, phenyl, fluorine,
hydroxyl, trifluoromethyl, (C1-C18)-alkylsulfinyl,
(C1-C18)-alkylsulfonyl, phenylsulfinyl, naphthyl-
sulfinyl, naphthylsulfonyl, (C11-C18)-alkoxy,
(C3-C8)-cycloalkoxy, (C ?C )?-alkoxy-(C -? )?-alkoxy,
-O-[CH2]x-CfH(2f+1-g)Fg apart from trifluoroethoxy,
pentafluoropropoxy and heptafluorobutoxy, phenyl-
(C2-C4)-alkoxy, phenoxy, (C1-C12)-alkanoyl, phenyl-
(C1-C4)-alkanoyl or benzoyl, where, in substituents
with a phenyl or naphthyl ring, this optionally
carries up to 5 identical or different substituents
from the series comprising fluorine, chlorine,
bromine, nitrile, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -O-[CH2]X-CfH(2f+1-g)Fg or (C1-C6)-
alkylsulfonyl, and

- 93 -
R4 is (C1-C18)-alkyl, (C2-C18)-alkenyl, (C2-C18)-
alkenyloxy, (C2-C18)-alkynyl, phenyl, chlorine,
fluorine, bromine, hydroxyl, trifluoromethyl,
(C1-C18)-alkylsulfinyl, (C1-C18)-alkylsulfonyl,
phenylsulfinyl, phenylsulfonyl, naphthylsulfinyl,
naphthylsulfonyl, (C1-C18)-alkoxy apart from
1-butoxy, (C3-C8)-cycloalkoxy, (C1-C8)-alkoxy-
(C1-C8)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, phenyl-
(C2-C4)-alkoxy, phenoxy, (C1-C12)-alkanoyl, phenyl-
(C1-C4)-alkanoyl or benzoyl, where, in substituents
with a phenyl or naphthyl ring, this optionally
carries up to 5 identical or different substituents
from the series consisting of fluorine, chlorine,
bromine, nitrile, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg or (C1-C6)-
alkylsulfonyl,
or a physiologically active salt thereof.
13. A compound of the formula I as claimed in claims 4
and 12, in which
m is 0,
A is a -CH2- group,
B is -CO2H,
R1 and R5 are hydrogen and
R2 is (C1-C18)-alkyl, (C1-C18)-alkenyl, phenyl,
chlorine, fluorine, bromine, trifluoromethyl,
(C1-C18)-alkylsulfinyl, (C1-C18)-alkylsulfonyl,
phenylsulfinyl, phenylsulfonyl, naphthylsulfinyl,
naphthylsulfonyl, (C1-C18) -alkoxy, (C3-C8)-cyclo-
alkoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy, -O-[CH2]x-
CfH(2f+1-g)Fg, where, in substituents having a phenyl
or naphthyl ring, this optionally carries up to 5
identical or different substituents from the series
consisting of fluorine, chlorine, bromine, nitrile,
trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,
-O-[CH2]x-CfH(2f+1-g)Fg and (C1-C6)-alkylsulfonyl, and
R3 is (C1-C18)-alkyl, (C1-C18)-alkenyl, phenyl,

- 94 -
fluorine, trifluoromethyl, (C1-C18)-alkylsulfinyl,
(C1-C18)-alkylsulfonyl, phenylsulfinyl, naphthyl-
sulfinyl, naphthylsulfonyl, (C11-C18)-alkoxy,
(C3-C8)-cycloalkoxy, (C1-C ?-alkoxy-(C ?C ?-alkoxy,
-O-[CH2]x-CfH(2f+1-g)Fg, apart from trifluoroethoxy,
pentafluoropropoxy and heptafluorobutoxy, phenyl-
(C2-C4)-alkoxy, phenoxy, (C1-C12)-alkanoyl, phenyl-
(C1-C4)-alkanoyl or benzoyl, where, in substituents
having a phenyl or naphthyl ring, this optionally
carries up to 5 identical or different substituents
from the series comprising fluorine, chlorine,
bromine, nitrile, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg and (C1-C6)-
alkylsulfonyl, and
R4 is (C1-C18)-alkyl, (C1-C18)-alkenyl, phenyl,
chlorine, fluorine, bromine, trifluoromethyl,
(C1-C18)-alkylsulfinyl, (C1-C18)-alkylsulfonyl,
phenylsulfinyl, phenylsulfonyl, naphthylsulfinyl,
naphthylsulfonyl, (C1-C18)-alkoxy apart from
1-butoxy, (C3-C8)-cycloalkoxy, (C1-C8)-alkoxy-
(C1-C8)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, phenyl-
(C2-C4)-alkoxy, phenoxy, (1l-C12)-alkanoyl, phenyl-
(C2-C4)-alkanoyl or benzoyl, where, in substituents
with a phenyl or naphthyl ring, this optionally
carries up to 5 identical or different substituents
from the series comprising fluorine, chlorine,
bromine, nitrile, trifluoromethyl, (C1-C6)-alkyl,
(cl-c6)-alkoxyl, -O-[CH2]x-CfH(2f+1-g)Fg or (C1-C6)-
alkylsulfonyl,
or a physiologically active salt thereof.
14. A compound of the formula I as claimed in claims 5
and 13, in which
m is 0,
A is a -CH2- group,
R1 and R5 are hydrogen,
one of the substituents R2, R3 or R4 is hydrogen and the
other two are identical or different and are hydrogen,

- 95 -
(C1-C16)-alkyl, fluorine, chlorine, bromine, trifluoro-
methyl, (C1-C16)-alkylsulfonyl, phenylsulfonyl, (C1-C16)-
alkoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy, -O-[CH2]x-
CfH(2f+1g)Fg, benzyloxy or phenoxy, where, in substituents
which contain a phenyl ring, this optionally carries up
to 3 substituents from the series comprising fluorine,
chlorine, bromine, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg or (C1-C4)-alkyl-
sulfonyl, or a physiologically active salt thereof.
15. A compound of the formula I as claimed in claims 6
and 14, in which
m is 0,
A is a -CH2- group,
R1, R2 and R5 are hydrogen and
R3 is (C1-C16)-alkyl, fluorine, trifluoromethyl,
(C1-C16)-alkylsulfonyl, naphthylsulfonyl, (C11-C16)-
alkoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy, -O-[CH2]x-
CfH(2f+1-g)Fg apart from trifluoroethoxy, pentafluoro-
propoxy and heptafluorobutoxy or phenoxy, where, in
substituents which contain a phenyl ring, this
optionally carries up to 3 substituents from the
series comprising fluorine, chlorine, trifluoro-
methyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, -O-[CH2]x-
CfH(2f+1-g)Fg and (C1-C4)-alkylsulfonyl, and
R4 is (C1-C16)-alkyl, fluorine, chlorine, trifluoro-
methyl, (C1-C16)-alkylsulfonyl, phenylsulfonyl,
naphthylsulfonyl, (C1-C16)-alkoxy apart from
1-butoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy or -O-[CH2]x-
CfH(2f+1-g)Fg, where, in substituents which contain a
phenyl ring, this optionally carries up to 3 sub-
stituents from the series consisting of fluorine,
chlorine, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-
alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg and (C1-C4)-alkyl-
sulfonyl, or a physiologically active salt thereof.
16. A compound of the formula I as claimed in claims 7
and 15, in which

- 96 -
m is 0,
A is a -CH2- group,
R1, R, R3 and R5 are hydrogen and
R4 is (C1-C12)-alkyl, fluorine, chlorine, bromine, tri-
fluoromethyl, (C1-C12)-alkylsulfonyl, phenylsulfonyl,
naphthylsulfonyl, (C1-C12)-alkoxy apart from 1-butoxy,
(C1-C6)-alkoxy-(C1-C6)-alkoxy, -O-[CH2]X-CfH(2f+1-g)Fg, or
phenoxy, where, in substituents which contain a phenyl or
naphthyl ring, this is optionally monosubstituted by
fluorine, chlorine, bromine, trifluoromethyl, (C1-C6)-
alkyl, (C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg or (C1-C4)-
alkylsulfonyl, or a physiologically active salt thereof.
17. A compound of the formula I as claimed in claims 8
and 16, in which
m is 0,
A is a -CH2- group,
R1, R3, R4 and R5 are hydrogen and
R is (C1-C12)-alkyl, fluorine, chlorine, bromine, tri-
fluoromethyl, (C1-C12)-alkylsulfonyl, phenylsulfonyl,
naphthylsulfonyl, (C1-C12)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-
alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg, benzyloxy or phenoxy,
where, in substituents which contain a phenyl or naphthyl
ring, this is optionally monosubstituted by fluorine,
chlorine, bromine, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -O-[CH2]x-CfH(2f+1-g)Fg or (C1-C4)-alkyl-
sulfonyl, or a physiologically active salt thereof.
18. A compound of the formula I as claimed in claims 9
and 17, in which
m is 0,
A is a -CH2- group,
R1, R and R5 are hydrogen,
R4 is hydrogen or chlorine and
R3 is hydrogen, fluorine, (C1-C4)-alkoxy-(C1-C6)-alkoxy,
-O-[CH2]x-CfH(2f+1-g)Fg apart from trifluorethoxy,
pentafluoropropoxy and heptafluorobutoxy, naphthyl-
sulfonyl or phenoxy, where, in substituents which
contain a phenyl or naphthyl ring, this optionally

- 97 -
carries up to 3 identical or different substituents,
preferably one substituent, from the series
comprising fluorine, chlorine, bromine,
trifluoromethyl, trifluoromethoxy, (C1-C6)-alkyl and
(C1-C6)-alkoxy, or a physiologically active salt
thereof.
19. A compound of the formula I as claimed in claims 10
and 18, in which
m is 0,
A is a -CH2- group,
R1, R2, R4 and R5 are hydrogen and
R3 is hydrogen, fluorine, (C1-C4)-alkoxy-(C1-C6)-alkoxy,
-O-[CH2]x-CfH(2f+1-g)Fg apart from trifluoroethoxy,
pentafluoropropoxy and heptafluorobutoxy, naphthyl-
sulfonyl or phenoxy, where, in substituents which
contain a phenyl or naphthyl ring, this optionally
carries up to 3 identical or different substituents,
preferably one substituent, from the series
comprising fluorine, chlorine, bromine,
trifluoromethyl, trifluoromethoxy, (C1-C6)-alkyl and
(C1-C6)-alkoxy, or a physiologically active salt
thereof.
20. A prodrug to a compound of the formula I as claimed
in claims 1 to 19.
21. A process for the preparation of a compound of the
formula I as claimed in claims 1 to 19, which comprises
1.i1.) reacting a quinoline-2-carboxylic acid of the
formula II (R11 = H) with an amino ester of the
formula III to give an amide ester of the formula
IV, or
1.i2.) reacting a quinoline-2-carboxylic acid ester of
the formula II (R11 = lower alkyl) under the
conditions of aminolysis to give a compound of
the formula IV; where R10 is PG (Protecting

- 98 -
Group) and A-B is (CH2)1-4-CO2H
<IMG> <IMG>
<IMG>
II IV
1.ii) liberating a compound of the formula I or V from
its ester of the formula IV or VI; and/or
<IMG> <IMG> <IMG>
VI I
<IMG> <IMG> <IMG>
IV V
1.iii) obtaining a compound of the formula I or VI from
a compound of the formula V or IV by splitting
off the hydroxyl-protecting group R10,
and if appropriate

- 99 -
<IMG> <IMG> <IMG>
V I
<IMG> <IMG> <IMG>
IV VI
1.iv) oxidizing a compound of the formula I, IV, V or
VI to give a compound of the formula Ia, IVa, Va
or VIa.
<IMG> <IMG> <IMG>
I Ia
22. A compound as claimed in claims 1 to 19 for use for
inhibiting collagen biosynthesis.
23. A compound as claimed in claims 1 to 19 as an
inhibitor of prolyl hydroxylase.
24. A compound as claimed in claims 1 to 19 for use as
a fibrosupressant.

- 100 -
25. A compound as claimed in claims 1 to 19 for the
preparation of a medicament against fibrotic diseases.
26. A compound as claimed in claims 1 to 19 for the
preparation of a medicament against fibrotic diseases of
the liver.
27. A compound as claimed in claims 1 to 19 for the
preparation of a medicament against fibrotic diseases of
the lung.
28. A compound as claimed in claims 1 to 19 for the
preparation of a medicament against fibrotic diseases of
the skin.
29. The use of a compound of the formula I as claimed in
claims 1 to 19 as an inhibitor of prolyl hydroxylase and
as a fibrosupressant.
30. A medicament comprising a compound of the formula I
as claimed in claims 1 to 19.
31. An intermediate product of the formula II
<IMG>
II
in which
R1 to R5 have the meanings which apply to a compound of
the formula I as claimed in claims 1 to 19,
R10 is hydrogen or an HO-protecting group and
R11 is hydrogen, (C1-C8)-alkyl or benzyl,

- 101 -
with the exception of compounds of the formula II in
which R10 is benzyl or methyl if R1 to R5 and R11 are
hydrogen, and those compounds of the formula II in which
R10 is hydrogen, benzyl or p-toluenesulfonyl if R1 to R5
are hydrogen and R11 is ethyl and those compounds of
formula II in which R3 is hydrogen or methoxy, if R1, R2,
R3 R4 R5 R10 and R11 are hydrogen.
32. An intermediate of the formula X
<IMG> (X)
in which
m is 0 or 1 and
R2 to R5 have the meanings which apply to a compound of
the formula I as claimed in claims 1 to 19,
with the exception of compounds of the formula X in which
m is 0, R3 is hydrogen, methyl or chlorine if R2, R4 and
R5 are hydrogen.

Description

218~717
.
HOECHST ARTIENGESELLSCHAFT HOE 95/F 224 R Dr. FI/St
Description
Substituted quinoline-2-carboxamides, their preparation
and their use as pharmaceuticals, and intermediates
The invention relates to substituted quinoline-2-
carboxylic acid amides, to their preparation and their
use ~s inhibitors of prolyl 4-hydroxylase, and to their
use as pharmaceuticals for the treatment of fibrotic
disea~es, as well as to intermediates in their
preparation.
Compounds which inhibit the enzymes prolyl and lysyl
hydroxylase have the effect of very selective inhibition
of collagen biosynthesis by influencing collagen-specific
hydroxylation reaction In the course thereof, protein-
bound proline or lysine is hydroxylated by the enzymesprolyl or lysyl hydroxylase. If this reaction is sup-
pressed by inhibitors, a nonfunctional hypohydroxylated
collagen molecule which can be released by the cells into
the extracellular space only in a small amount is formed.
The hypohydroxylated collagen furthermore cannot be
incorporated into the collagen matrix and is very readily
degraded proteolytically. As a consequence of these
effects, the amount of collagen deposited extracellularly
is reduced overall.
Inhibitors of prolyl hydroxylase are therefore suitable
substances in the treatment of diseases in which the
deposition of collagens contributes decisively to the
clinical picture. These include, inter alia, fibroses of
the lung, liver and skin (scleroderma and scarring after
burns, injuries and surgical operations) and
atherosclerosis.
lt is known that the enzyme prolyl hydroxylase is
inhibited effectively by pyridine-2,4- and -2,5-

2186717
-- 2
dicarboxylic acid (R. Majamaa et al., Eur. J. Biochem.
138 (1984) 239-245). However, these compounds are active
as inhibitors in the cell culture only at very high
concentrations (Tschank, G et al., Biochem. J. 238 (1987)
625 to 633).
Prodrugs of pyridine-2,4(5)-dicarboxylates are also
known. These are described in EP-A-0 590 520 and
EP-A-0 562 512.
N-Oxalylglycines as inhibitors of prolyl 4-hydroxylase
are known from J. Med. Chem. 1992, 35, 2652 to 2658
(Cunliffe et al.), and EP-A-0 457 163 (Baader et al.).
3-Hydroxypyridine-2-carboxylic acid N-(carboxymethyl)-
amide is known from G. Yolles et al. in: Bull. Soc. Chim.
Fr. 1965, 8, 2252 to 2259.
Hydroxyisoquinoline- and hydroxycinnolinecarboxylic acid
glycylamides are known from Biochem. Soc. Trans. 1991,
19, 812 to 815 (Franklin et al.).
EP-A-0 661 269 describes substituted heterocyclic carb-
oxylic acid amides and their use as inhibitors of prolyl
4-hydroxylase and as inhibitors of collagen biosynthesis.
The object was to search for even more active inhibitors
of prolyl hydroxylase and for other inhibitors of
collagen biosynthesis.
It has now been found that a selection of the compounds
included in EP-A-0 661 269, that is to say the quinoline-
2-carboxylic acid amides having an OH function in the
ortho position relative to the amide function, show a
surprisingly high inhibition of prolyl 4-hydroxylase in
cell cultures.
The compounds according to the invention correspond to
the formula (I)

- 2186717
R ~ ~, ~ ~ NH-A-B (Ij
()m
in which
A is (Cl-C4)-alkylene, which is optionally substituted
by one or two substituents from the series consist-
ing of halogen, cyano, nitro, trifluoromethyl,
~C1-C6)-alkyl, (Cl-C6)-hydroxyalkyl, (C1-C6)-alkoxy,
-o-tcH2]x-cfH(2f+l-g)Halg~ preferably (Cl-C8)-fluoro-
alkoxy, (Cl-C8)-fluoroalkenyloxy, (Cl-C8)-fluoro-
alkynyloxy, -OCF2Cl or -0-CF2-CHFCl, (Cl-C6)-alkyl-
mercapto, (Cl-C6)-alkylsulfinyl, (Cl-C6)-alkyl-
sulfonyl, (Cl-C6)-alkylcarbonyl, (Cl-C6)-alkoxy-
carbonyl, carbamoyl, N-(Cl-C4)-alkylcarbamoyl, N,N-
di-(Cl-C4)-alkylcarbamoyl, (Cl-C6)-alkylcarbonyloxy,
(C3-C8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyl-
oxy, anilino, N-methylanilino, phenylmercapto,
phenylsulfonyl, phenylsulfinyl, sulfamoyl,
N-(Cl-C4)-alkylsulfamoyl and N,N-di-(Cl-C4)-
alkylsulfamoyl, or
by a (C6-Cl2)-arYloxy~ (c7-cll)-aralkyloxy~ (C6-C12)-
aryl or (C7-C11)-aralkyl radical, which carries, in
the aryl part, 1, 2, 3, 4 or 5 identical or
different substituents from the series consisting of
halogen, cyano, nitro, trifluoromethyl, (C1-C6)-
alkyl, (C1-C6)-alkoxy, ~0-tcH2]x-cfH~2f+l-g)Halg~
-OCF2Cl,-0-CF2-CHFCl, (C1-C6)-alkylmercapto, (C1-C6)-
alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkyl-
carbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl,
N-(Cl-C4)-alkylcarbamoyl, N,N-di-(Cl-C4)-alkyl-
carbamoyl, (C1-C6)-alkylcarbonyloxy, ( C3 -C8 ) - CyC lo-
alkyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl and N,N-
di-(Cl-C4)-alkylsulfamoyl, or

- 2~6717
by one or more substituents Rx of the a-C atom of an
a-amino acid, it being possible for the naturally
occuring L-amino acids and their D isomers to be
used;
B is an acid grouping from the series comprising
-CO2H, -CONHCOR"', -CONHSOR"', CONHSO2R"', -NHSO2CF3,
tetrazolyl, imidazolyl and 3-hydroxyisoxazolyl, in
which R"' is aryl, heteroaryl, (C3-C7)-cycloalkyl or
(C1-C4)-alkyl, optionally monosubstituted by
(C6-C12)-aryl, heteroaryl, OH, SH, (C1-Cg)-alkyl,
(C1-C4)-alkoxy, (C1-C )4-thioalkyl, -sulfinyl or
-sulfonyl, CF3, Cl, Br, F, I, NO2, -COOH, (C2-C5)-
alkoxycarbonyl, NH2, mono- or di-(C1-C4-alkyl)-amino
or (C1-C4)-perfluoroalkyl,
R1, R2, R3, R4 and R5 are identical or different and are
hydrogen, hydroxyl, halogen, cyano, trifluoromethyl,
nitro, carboxyl, (C1-C20)-alkyl, (C3-C8)-cycloalkyl,
(C3~Cs)~cYcloalkyl-(cl-cl2)-alkyl~ ( C3 -C8 ) -cyclo-
alkoxy, (C3-C8)-cycloalkyl-(C1-C12)-alkoxy, (C3-C8)-
cycloalkyloxy-(C1-C12)-alkyl, (C3-C8)-cycloalkyloxy-
(cl-cl2)-alkoxy~ (C3-C8)-cycloalkyl-(C1-C8)-alkyl-
(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy-
(C1-C6)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-
(C1-C6)-alkyl, (C3~C8)~cYcloalkoxy-(cl-c8)-alk
(C1-C8)-alkoxy, (C6-C12)-aryl, (c7-cl6)-aralk
(C7-C16)-aralkenyl, (c7-cl6)-aralkynyl~ (C2-c20)
alkenyl, (c2-c2o)-alkynyl~ (C1-C20)-alkXY~ (C2 C20)
alkenyloxy, (C2-C20)-alkynyloxy, retinyloxy,
(cl-c2o)-alkoxy-(cl-cl2)-alkyl~ (cl-cl2)-alk
(C1-C12)-alkoxy~ (cl-cl2)-alkoxy-(cl-c8)-alk
(C1 C8) alkyl~ (C6-Cl2)-arYloxy~ (c7-cl6)-aralkyloxy~
(c6-cl2)-aryloxy-(cl-c6)-alkoxy, (C7-cl6)-aralkoxy-
(Cl-C6)-alkoxy, (Cl-Cl6)-hydroxyalkyl, (C6-Cl6)-
aryloxy-(C1-C8)-alkyl, (C7-C16)-aralkoXy-(cl-c8)
alkyl, (C6-C12)-aryloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl,
(C7-C12)-aralkyloxy-(C1-C8)-alkoxy-(C1-C6)-alkyl,
(c2-c2o)-alkenyloxy-(cl-c6)-alkyl~ (C2-C20)-

- 2186717
alkynyloxy-(C1-C6)-alkyl, retinyloxy-~C1-C6)-alkyl,
tCH2-]xCfH(2f+l-g)Halg~ (cl-c6)-chlorofluoroalk
such as -OCF2Cl, -OCF2-CHFCl,
~Cl-C20)-alkylcarbonyl, ( C3-C ~ -cycloalkylcarbonyl,
(C6-C12)-arylcarbonyl, (C7-Cl6)-aralkylcarbonyl,
cinnamoyl, (C2-C20)-alkenylcarbonyl, (C2-C20)-
alkynylcarbonyl,
(C2-C20)-alkoxycarbonyl, (cl-cl2)-alkoxy-(cl-cl2)-
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, (C7-Cl6)-
aralkoxycarbonyl, ( C3-C8)-CyC loalkoxycarbonyl,
(C2-C20)-alkenyloxycarbonyl, retinyloxycarbonyl,
(C2-C20)-alkynyloxycarbonyl, (C6-C12)-aryloxy-
(C1-C6)-alkoxycarbonyl, (c7-cl6)-aralkoxy-(cl-c6)-
alkoxycarbonyl, (C3-C8)-cycloalkyl-(Cl-C6)-alkoxy-
carbonyl, (C3-C8)-cycloalkoxy-(C1-C6)-alkoxycarbonyl,
(C1-Cl2)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-
carbonyloxy, (C6-Cl2)-arylcarbonyloxy, (C7-Cl6)-
aralkylcarbonyloxy, cinnamoyloxy, (C2-Cl2)-alkenyl-
carbonyloxy, (C2-C12)-alkynylcarbonyloxy,
(Cl-C12)-alkoxycarbonyloxy, (Cl-Cl2)-alkoxy-(Cl-Cl2)
alkoxycarbonyloxy, (C6-Cl2)-aryloxycarbonyloxy,
(C7-Cl6)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxy-
carbonyloxy, (C2-C12)-alkenyloxycarbonyloxy,
(C2-C12)-alkynyloxycarbonyloxy,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-
(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-
carbamoyl, N,N-dicyclo-( C3 -C8 ) -alkylcarbamoyl,
N-(Cl-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl,
N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl,
N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(Cl-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl,
N-(C6-Cl2)-arylcarbamoyl, N-( C7 -C1 6 ) -aralkyl-
carbamoyl, N-(Cl-C10)-alkyl-N-(C6-Cl6)-arylcarbamoyl,

- 21 8671 7
N-~C1-C10)-alkyl-N-(C7-C16)-aralkylcarbamoyl,
N-((C1-C12)-alkoxy-(C1-C10)-alkyl)carbamoyl,
N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl,
N-(( C7 -C16 ) -aralkyloxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((C1-C10)-alkoxy-(C1-C10)-
alkyl)carbamoyl, N-(C1-C1o)~alkyl-N-((C6-C12)_
aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-
( (C7 -Cl6 ) -aralkyloxy-(C1-C10)-alkyl)carbamoyl,
CON(CH2)h, in which a CH2 group can be replaced by
O, 8, N-(C1-C8)-alkylimino, N-(C -~ )~cycloalkyl-
imino, N-(C3-C8)-cycloalkyl-(C1C 12) -alkylimino, N-
(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or N-
(C1-C12)-alkoxy-(C1-C6)-alkylimino and h is 3 to 7,
or a carbamoyl radical of the formula J
_ _
RX H
C O . ~R ~ T
o
--S
in which
RY is the substituent of an L- or D-a-amino acid,
s is 1, 2, 3, 4 or 5 and
T is OH, OR or NR R , in which
R , R and R are identical or different and are
hydrogen, (c6-cl2)-aryl~ (C7-C11)-aralkyl,
(C1-C8)-alkyl, (C3-C8)-cycloalkyl, (+)-dehydro-
abietyl, (C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-
aralkoxy-(C1-C8)-alkyl, (c6-cl2)-aryloxy-
~C1-C8)-alkyl, (Cl-C10)-alkanoyl, optionally
substituted (C7-C16)-aralkanoyl or optionally
substituted (C6-Cl2)-aroyl, or
R and R together are -[CH2]h, in which one CH2
group can be replaced by O, S, SO, SO2,

- 2 1 8 67 1 7
N-acylamino, N-(C1-C10)-alkoxycarbonylimino, N-
(C1-C8)-alkylimino, N-(C3-C8)-cycloalkylimino, N-
(C3-C8)-cycloalkyl-(C1-C4)-alkylimino, N-(C6-C12)-
arylimino, N-(C7-C16)-aralkylimino or N-(C1-C4)-
S alkoxy-(C1-C6)-alkylimino and h is 3 to 7,
or further wherein R1 R2 R3 R4 and R5 are
identical or different and are:
carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-
~C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-
carbamoyloxy, N-(C 6 - C 12 ) - arylcarbamoyloxy,
N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-
(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-
(C7-C16)-aralkylcarbamoyloxy, N-((Cl-clO)-
alkyl)carbamoyloxy, N-((c6-cl2)-aryloxy-(cl-clo)
alkyl)carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyloxy, N-(cl-clo)-alkyl-N-((cl-clo)
alkoxy)-(C1-C10)-alkyl)carbamoyloxy, N-(Cl-clo)
alkyl-N-((c6-cl2)-aryloxy)-(cl-clo)-alkyl)-
carbamoyloxy, N-(C1-C1o)~alkyl-N-((C7-C16)_
aralkyloxy-(C1-C10)-alkyl)carbamoyloxy,
NRYRZ,wherein RY and RZ are independently selected
from (C1-C12)-alkyl~ (C3-C8)-cycloalkyl, (C3-C12)-
alkenyl, (c3-C12)-alkynyl, (C6-C12)-arYl~ (C7-C11)-
aralkyl, (C1-C12)-alkoxy,(C7-C12)-aralkoxy,
(C1-C12)-alkanoyl, (C3-C8)-cycloalkanoyl, (C6-C12)-
aroyl, (C7-C16)-aralkanoyl, and further wherein RY
and RZ together are -~CH2]h-, wherein one CH2-group
can be replaced by O, S, N-(C1-C4)-alkylcarbonyl-
imino or N-(C1-C4)-alkoxycarbonylimino, and h is 3
to 6,
(C1-C12)-alkanoylamino-(C1-C8)-alkyl, (C3-C8)-cyclo-
alkanoylamino-(C1-C8)-alkyl, (C6-C12)-aroylamino-
(C1-C8)-alkyl, ( C7-Cl6) -aralkanoylamino-(C1-C8)-
alkyl, amino-(C1-C10)-alkyl, N-(C1-C10)-alkylamino-

- 21867~7
(C1-C10)-alkyl, N,N-di(C1-C10)-alkylamino-(Cl-ClO)-
alkyl, (C3-C8)-cycloalkylamino-(C1-C10)-alkyl,
(C1-C20)-alkylmercapto, (C1-C20)-alkylsulfinyl,
(cl-c2o)-alkylsulfonyl~ (C6-C12)-arylmercapto,
(C6-C12)-arylsulfinyl, (C6-C12)-arylsulfonyl,
(C7-C16)-aralkylmercapto, (C7-Cl6)-aralkylsulfinyl,
(C7-C16)-aralkylsulfonyl, (Cl-C12)-alkylmercapto-
(C1-C6)-alkyl, (cl-cl2)-alkylsulfinyl-(cl-c6)-alkyl~
(C1-C12)-alkylsulfonyl-(C1-C6)-alkyl, (C6-C12)-aryl-
mercapto-(C1-C6)-alkyl, (C6-C12)-arylsulfinyl-
(C1-C6)-alkyl, (c6-cl2)-arylsulfonyl-(cl-c6)-alkyl~
(C7-C16)-aralkylmercapto-(C1-C6)-alkyl, (C7-C16)-
aralkylsulfinyl-(C1-C6)-alkyl, (C7-C16)-aralkyl-
sulfonyl-(C1-C6)-alkyl,
sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-
(Cl-C10)-alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl,
N-(C6-C12)-arylsulfamoyl, N-(C7-C16)-aralkylsulf-
amoyl, N-(C1-C )l~lkyl-N-(C -C6 )l~rylsulfamoyl,
N-(C1-C10)-alkyl-N-(C7-Cl6)-aralkylsulfamoyl,
(C1-C10)-alkyl-sulfonamido, N-((cl-clo)-alkyl)
(C1-C10)-alkylsulfonamido, (C7-C16)-aralkyl-
sulfonamido, or N-(C1-C10)-alkyl-(C 7C 1~-aralkyl-
sulfonamido,
where the radicals which contain an aryl radical can
in turn be substituted on the aryl by 1 to 5 ident-
ical or different radicals from the series
comprising:
hydroxyl, halogen, cyano, trifluoromethyl, nitro,
carboxyl, (cl-cl6)-alkyl~ (C3-C8)-cycloalkyl,
(c3-c8)-cycloalkyl-(cl-cl2)-alkyl~ (C3-C8)-cyclo-
alkoxy~ (c3-c8)-cycloalkyl-(cl-cl2)-alkoxy~ (C3-C8)-
cycloalkyloxy-(c1-c12)-alkyl, (C3-C8)-cycloalkyloxy-
(cl-cl2)-alkoxy~ (C3-C8)-cycloalkyl-(C1-C8)-alkyl-
(C1-C6)-alkoxy, (C3-C8)-cycloalkyl-(C1-C8)-alkoxy-
(C1-C6)-alkyl, (C3-C8)-cycloalkyloxy-(C1-C8)-alkoxy-
(C1-C6)-alkyl, (C3-C8)-cycloalkoxy-(C1-C8)-alkoxy-
(Cl-C8)-alkoxy, (c6-cl2)-aryl~ (C7-Cl6)-aralkyl,
(C2-C16)-alkenyl, (C2-C12)-alkynyl, (Cl-Cl6)-alkoxy,

2186717
g
(C1-C16)-alkenyloxy, (C1-C12)-alkoxy-(C1-C12)-alkyl,
(cl-cl2)-alkoxy-(cl-cl2)-alkoxy~ (C1-C12)-alkoxy-
(cl-c8)-alkoxy-(cl-c8)-alkyl~ (c6-cl2)-aryloxy~
(C7-C16)-aralkyloxy, (C6-C12)-aryloxy-(C1-C6)-alkoxy,
S (c7-cl6)-aralkoxy-(cl-c6)-alkoxy, (C1-Cg)~hYdrXY~
alkyl, (C6~Cl6)~arYloxy-(cl-c8)-alkyl~ (C7-C16)-
aralkoxy-(C1-C8)-alkyl, (c6-cl2)-aryloxy-(cl-c8)
alkoxy-(C1-C6)-alkyl, (c7-cl2)-aralkyloxy-(cl-c8)
alkoxy-(cl-c6)-alkyl~ -~tCH2-]xCfH(2f+1-g)Fg~ -OCF2Cl~
-OCF2-CHFCl,
(Cl-C12)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl,
(C6-C12)-arylcarbonyl, (C7-C16)-aralkylcarbonyl,
(C1-C12)-alkoxycarbonyl, (cl-cl2)-alkoxy-(cl-cl2)
alkoxycarbonyl, (C6-C12)-aryloxycarbonyl, ( C7 -Cl 6 ) -
aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl,
(C2-C12)-alkenyloxycarbonyl, (C2-C12)-alkynyloxy-
carbonyl, (c6-cl2)-aryloxy-(cl-c6)-alkoxycarbonyl~
(C7-C16)-aralkoxy-(C1-C6)-alkoxycarbonyl, (C3-Cg)-
cycloalkyl-(C1-C6)-alkoxycarbonyl, (C3-C8)-cyclo-
alkoxy-(C1-C6)-alkoxycarbonyl,
(C1-C12)-alkylcarbonyloxy, (C3-C8)-cycloalkyl-
carbonyloxy, (C6-C12)-arylcarbonyloxy, (C7-C16)-
aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)-alkenyl-
carbonyloxy, (C2-C12)-alkynylcarbonyloxy,
(C1-C12)-alkoxycarbonyloxy, (C1-C12)-alkXY-(Cl-cl2)-
alkoxycarbonyloxy, (C6-C12)-aryloxycarbonyloxy,
(C7-C16)-aralkyloxycarbonyloxy, (C3-C8)-cycloalkoxy-
carbonyloxy, (C2-C12)-alkenyloxycarbonyloxy,
(C2-C12)-alkynyloxycarbonyloxy,
carbamoyl, N-(C1-C12)-alkylcarbamoyl, N,N-di-
(C1-C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkyl-
carbamoyl, N,N-dicyclo-( C3 -C8 ) -alkylcarbamoyl,
N-(cl-clo)-alkyl-N-(c3-c8)-cycloalkylcarbamoyl~
N-((C3-C8)-cycloalkyl-(C1-C6)-alkyl)carbamoyl,

2186717
-- 10 --
N-(C1-C6)-alkyl-N-~(C3-C8)-cycloalkyl-(C1-C6)-
alkyl)carbamoyl, N-(+)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl,
N-(C6-C12)-arylcarbamoyl, N-(C7-C16)-aralkylcarb-
amoyl, N~(C1~C1o)-alkYl-N-(C6-C16)-arylcarbamOyl,
N-(cl-clo)-alkyl-N-(c7-cl6)-aralkylcarbam
N-((cl-cl6)-alkoxy-(cl-clo)-alkyl)carbam
N~((C6~C16)~arYlXY-(C1-C1O)-alkyl)carbamoyl,
N-((C7 -C16 ) -aralkyloxy-(C1-C10)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((Cl-ClO)-alkoxy-(Cl-ClO)-
alkyl)carbamoyl, N-(C1-C1o)~alkyl-N-((C -C 6 )
aryloxy-(C1-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-
((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl,
CON(CH2)h, in which one CH2 group can be replaced by
O, S, N-(C1-C8)-alkylimino, N-(C3-C8)-cycloalkyl-
imino, N-(C3-C8)-cycloalkyl-(C1-C4)-alkylimino,
N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or
N-(C1-C4)-alkoxy-(C1-C6)-alkylimino and h is 3 to 7,
carbamoyloxy, N-(C1-C12)-alkylcarbamoyloxy, N,N-di-
(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)-cycloalkyl-
carbamoyloxy, N-(C6-C16)-arylcarbamoyloxy,
N-(C7-C16)-aralkylcarbamoyloxy, N-(C1-C10)-alkyl-N-
(C6-C12)-arylcarbamoyloxy, N-(C1-C10)-alkyl-N-
( C 7 - C 1 6 ) - aralkylcarbamoyloxy, N-((C1-C )lo
alkyl)carbamoyloxy, N-((C6-Cl2)-aryloxy-(cl-clo)-
alkyl)carbamoyloxy, N-((C7-C16)-aralkyloxy-(C1-C10)-
alkyl)carbamoyloxy, N-(cl-clo)-alkyl-N-((cl-clo)
alkoxy-(C1-C10)-alkyl)carbamoyloxy, N-(Cl-clO)
alkyl-N-((c6-cl2)-aryloxy-(cl-clo)-alkyl)car
bamoyloxy, N-(C1-C10)-alkyl-N-((C7-Cl6)-aralkyloxy-
(C1-C10)-alkyl)carbamoyloxy,
amino, (C1-C12)-alkylamino, di-(C1-C12)-alkylamino,
(C3-C8)-cycloalkylamino, (C3-C12)-alkenylamino,
(C3-C12)-alkynylamino, N-(C6-C12)-arylamino,
N-(C7-C11)-aralkylamino, N-alkyl-aralkylamino,
N-alkyl-arylamino, (C1-C12)-alkoxyamino, (C1-C12)-
alkoxy-N-(C1-C10)-alkylamino,

2 ! ~
-- 11 --
(Cl-C12)-alkanoylamino, (C3-C8)-cycloalkanoylamino,
~C6-C12)-aroylamino, (C7-C16)-aralkanoylamino,
(C1-C12)-alkanoyl-N-~C1-C10)-alkylamino, (C3-C8)-
cycloalkanoyl-N-(C1-C10)-alkylamino, (C6-C12)-aroyl-
N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)-
alkylamino,
(Cl-Cl2)-alkanoylamino-(Cl-C8)-alkyl, (C3-C8)-cyclo-
alkanoylamino-(Cl-C8)-alkyl, (C6-Cl2)-aroylamino-
(Cl-C8)-alkyl, (C7-C16)-aralkanoylamino-(Cl-C8)-
alkyl, amino-(Cl-C10)-alkyl, N-(Cl-C10)-alkylamino-
(Cl-C10)-alkyl, N,N-di-(Cl-C10)-alkylamino-(Cl-ClO)-
alkyl, (C3-C8)-cycloalkylamino-(Cl-C10)-alkyl,
(C1-C12)-alkylmercapto, (C1-C12)-alkylsulfinyl,
(Cl-Cl2)-alkylsulfonyl, (C6-Cl6)-arylmercapto,
(C6-Cl6)-arylsulfinyl, (C6-C16)-arylsulfonyl,
(C7-C16)-aralkylmercapto, (C7-C16)-aralkylsulfinyl
and (C7-C16)-aralkylsulfonyl, or optionally carries
up to 3 of said radical substituents for said aryl
and two adjacent carbon atoms of an arylalkoxy
radical, recited in the definition of Rl-R5 together
carry a chain -tCH2]- and/or -CH=CH-CH=CH, where one
CH2-group of the chain is optionally replaced by 0,
S, S0, S02 or NR',
Rl and R2, R2 and R3, R3 and R4, or R4 and R5 form a chain
tCH2]o~ in which one or two CH2 groups of the chain,
which is saturated or unsaturated with a C=C double
bond, are optionally replaced by 0, S, S0, S02 or
NR', in which o is 3, 4 or S, and
R' is hydrogen, (C6-C12)-aryl, (C1-C8)-alkyl, (Cl-C8)-
alkoxy-(Cl-C8)-alkyl, (c7-cl2)-aralkoxy-(cl-c8)-
alkyl, (C6~Cl2)~arYloxy-(cl-c8)-alkyl~ (C1-C10)-
alkanoyl, optionally substituted (C7-C16)-aralkanoyl
or optionally substituted (C6-C12)-aroyl, and
m is 0 or 1,

- 2 1 867 1 7
- 12 -
f is 1 to 8,
g is 0 or 1 to (2f + 1),
x is 0 to 3 and
h is 3 to 6, including the physiologically active
salts.
Aryl is understood as meaning, in particular, phenyl and
naphthyl which are unsubstituted or preferably substi-
tuted as described, heteroaryl is understood as meaning,
in particular, pyridyl, picolyl or thienylmethyl which
are unsubstituted or substituted as described, cycloalkyl
is preferably understood as meaning cyclohexyl and
halogen is understood as meaning, in particular, fluor-
ine, chlorine and bromine.
The invention furthermore relates to salts of the com-
pounds of the formula I.
The salt formation with basic reagents can take place on
one or two acid groups of the compounds of the formula I,
i.e. on the radicals B, Rl, R2, R3, R4 and R5 and/or on
the acid phenolic OH group, in particular on the radicals
B and the phenolic OH group.
Reagents which are used are, for example, alcoholates,
hydroxides, carbonates, bicarbonates, hydrogen phosphates
and/or metal-organyls of the alkali metal and alkaline
earth metal elements, the elements of main groups 3 and
4 of the periodic table and the elements of the transi-
tion metals,
amines, optionally mono- to trisubstituted by (C1-C8)-
hydroxyalkyl, ~C1-C4)-alkoxy-(Cl-C8)-alkyl, phenyl, benzyl
or (C1-C8)-alkyl, which can be mono- to trisubstituted by
hydroxyl or (C1-C4)-alkoxy,
for example Tromethane (Tris buffer), 2-aminoethanol,
3-aminopropanol, hydroxylamine, dimethylhydroxylamine,
2-methoxy-ethylamine and 3-ethoxypropylamine, and

2186717
- 13 -
basic amino acids and derivatives, such as amino acid
esters, histidine, arginine and lysine and derivatives
thereof, and
medicaments which contain a basic group, such as, for
example, amiloride, verapamil and beta-blockers.
The invention furthermore relates to the compounds
according to the formula I for use as medicaments.
Compounds of the formula I which are of particular
importance are those in which
10 A is (C1-C3)-alkylene, which is optionally mono-
substituted by halogen, cyano, trifluoromethyl,
(Cl-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy
or -o-tcH2]x-cfH(2f+l _g) Fg or
A is -CHRX-, in which Rx is one of the substituents of
the ~-C atom of an ~-amino acid, in particular of a
naturally occuring L-amino acid or its D isomer,
B is -CO2H,
R1 and R5 are identical or different and are hydrogen,
(C1-C12)-alkyl, ~C1-C12)-alkenyl, chlorine, fluorine,
bromine, trifluoromethyl, ~Cl-C12)-alkylsulfonyl,
(C1-C12)-alkylsulfinyl, phenylsulfonyl or phenyl-
sulfinyl; where phenyl is optionally substituted by
fluorine, chlorine or (C1-C5)-alkoxy, (C1-C10)-
alkoxy, o-tcH2]x-c H f (2f+1~g~ g (C -C )-~lk~xy-
(C1-C6)-alkoxy or (C3-C8)-cycloalkoxy,
R2, R3 and R4 are identical or different and are hydro-
gen, hydroxyl, (C1-C20)-alkyl, (C2-C20)-alkenyl,
~C2-C20)-alkYnyl~ (Cl-C20)-alkoxy, (C2-C20)-alkenyl-
oxy, (C2-C20)-alkynyloxy, retinyloxy, (C1-C20)-
alkoxy-(Cl-C8)-alkyl, ~c2-c20)-alkenyloxy-~cl-cg)-
alkyl, retinyloxy-(C1-C6)-alkyl, ~C2-C20)-alkynyloxy-
~C1-C8)-alkyl, halogen, cyano, trifluoromethyl,

- 2~67i7
(C1-C12)-hydroxyalkyl, (C1-C20)-alkanoyl, ( C7 -Cl 6 ) -
aralkanoyl, ( C6 -Cl2 ) -aroyl, ( C6 -Cl2 ) -aryl~ (C 7-C 16) -
aralkyl, -o-tcH2]x-cfH(2f +1 _g) Fs~ (C1-C18)-alkyl-
mercapto, (C1-C18)-alkylsulfinyl, ~C ~C ~8-alkyl-
sulfonyl, ~C6-C12)-arylmercapto, ~C 6-Cl2)-aryl-
sUlfinyl)~ ~C6~C12)-arylsulfonyl~ ~C7-C12)-aralkyl-
mercapto, ~C7-C12)-aralkylsulfinyl, ~C7-C12)-aralkyl-
sulfonyl, ~C6-C ~aryloxy, ~C -C )-ar7al~10xy,
carboxyl, ~C1-C20)-alkoxycarbonyl, ~C1-C12)-alkoxy-
~C1-C12)-alkoxycarbonyl, (C6-C12)-aryloxycarbonyl,
(C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxy-
carbonyl, (C2-C20)-alkenyloxycarbonyl, retinyloxy-
carbonyl, (C2-C20)-alkynyloxycarbonyl, ~ C3 - C 8 ) - CyC lo-
alkyl-~C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkoxy-
~C1-C6)-alkoxycarbonyl, ~c6-cl2)-aryloxy-~cl-c6)
alkoxycarbonyl, ~c7-cl6)-aralkoxy-~cl-c6)
alkoxycarbonyl,
(cl-cl2)-alkoxy-(cl-cl2)-alkyl~ ~C1-C12)-alkoxy-
(C1-C12)-alkoxy, (cl-cl2)-alkoxy-(cl-cl2)-alkoxy-
(C1-C6)-alkyl, ~C7-C11)-aralkyloxy, ~C3-C8)-cyclo-
alkyl, ~C3-C8)-cycloalkyl-~C1-C12)-alkYl, (C3-C8)-
cycloalkyloxy, ~C3-C8)-cycloalkyl-~C1-C8)-alkoxy,
(C3-C8)-cycloalkyloxy-(C1-C12)-alkyl, ~C3-C8)-cyclo-
alkyloxy-(C1-C8)-alkoxy, (C3-C8)-cycloalkyl-(C1-C12)-
alkyl-(C1-C6)-alkoxy, (c3-c8)-cycloalkyl-(c -C1)-6
alkoxy-~C1-C6)-alkyl, ~C3-C8)-cycloalkoxy-(C1-C6)-
alkoxy-(C1-C6)-alkyl, NRYRZ, substituted (C6-C12)-
aryloxy-(C1-C6)-alkyl, ~C7-C11)-aralkoxy-~C1-C6)-
alkyl, ~C6-C12)-aryloxy-~C1-C6)-alkoxy-~C1-C6)-alkyl,
(C7-C11)-aralkyloxy-~C1-C6)-alkoxy-~C1-C6)-alkyl,
(C6~C12)-aryloxy-(Cl-C6)-alkoxy or (C7-C1l)-aralkoxy-
(C1-C6)-alkoxy,
carbamoyl, N-~Cl-Cl2)-alkylcarbamoyl, N,N-di-
~Cl-C12)-alkylcarbamoyl, N-~C3-C8)-cycloalkyl-
carbamoyl, N,N-dicyclo~C3-C8)-alkylcarbamoyl,
N-(C1-C10)-alkyl-N-~C3-C8)-cycloalkylcarbamoyl,
N-(C3-C8)-cycloalkyl-~Cl-C16)-alkyl)carbamoyl,

2 1 8b~ ~ 7
-- 15 --
N-(C1-C6)-alkyl-N-((C3-C8)-cycloalkyl-(Cl-C6)-
alkyl)carbamoyl, N-(~)-dehydroabietylcarbamoyl,
N-(C1-C6)-alkyl-N-(+)-dehydroabietylcarbamoyl,
N-(C6-C12)-arylcarbamoyl, N- (C7 -C16 ) -aralkyl-
carbamoyl, N-(C1-C10)-alkyl-N-(C6-Cl6)-arylcarbamoyl,
N-(C1-C10)-alkyl-N- (C7 -C16 ) -aralkylcarbamoyl,
N-((C1-C12)-alkoxy-(C1-C10)-alkyl)carbamoyl,
N-((C6-C16)-aryloxy-(C1-C10)-alkyl)carbamoyl,
N-((C7 -C16 ) -aralkyloxy-(C1-C6)-alkyl)carbamoyl,
N-(C1-C10)-alkyl-N-((Cl-ClO)-alkoxy-(Cl-ClO)-
alkyl)carbamoyl, N-(C1-C )~lkyl-N-((C -C 6 )
aryloxy-(Cl-C10)-alkyl)carbamoyl, N-(C1-C10)-alkyl-N-
((C7-C16)-aralkyloxy-(C1-C10)-alkyl)carbamoyl, or
CON(CH2)h, in which one CH2 group can be replaced by
O, S, N-(C1-C16)-alkylimino, N-(C3-C8)-cycloalkyl-
imino, N-(C3-C8)-cycloalkyl-(C1-C12)-alkylimino,
N-(C6-C12)-arylimino, N-(C7-C16)-aralkylimino or
N-(Cl-Cl2)-alkoxy-(Cl-C6)-alkylimino and h is 3 to 7,
where an aromatic radical carries 1, 2, 3, 4 or S
identical or different substituents from the series
comprising hydrogen, halogen, cyano, nitro,
hydroxyl, trifluoromethyl, (C1-C16)-alkyl, (C2-C16)-
alkenyl, (C1-C6)-hydroxyalkyl, (C1-Cl6)-alko
(cl-cl6)-alkenyloxy~ ~~tCH2]xCfH(2~+1-g)Fs~ OCF2Cl,
-O-CF2-CHFCl, (C1-C6)-alkylmercapto, (Cl-C6)-
alkylsulfinyl, (Cl-C6)-alkylsulfonyl, (C1-C6)-
alkylcarbonyl, (C1-C6)-alkoxycarbonyl, carbamoyl, N-
(C1-C4)-alkylcarbamoyl, N,N-di-(C1-C4)-
alkylcarbamoyl, (C1-C6)-alkylcarbonyloxy, (C3-C8)-
cycloalkylcarbamoyl, phenyl, benzyl, phenoxy,
benzyloxy, phenylmercapto, phenylsulfonyl,
phenylsulfinyl, sulfamoyl, N-(C1-C4)-alkylsulfamoyl
and N,N-di-(C1-C4)-alkylsulfamoyl, or optionally
carries up to 3 of the abovementioned identical or
different substituents and two adjacent carbon atoms
of the aralkyloxy radical recited in the definition
of R1-R5 together carry a chain -tCH2]- and/or -
CH=CH-CH=CH-, where one CH2 group of the chain is
optionally replaced by O, S, SO, SO2 or NR',

2 1 867 1 7
- 16 -
RY and RZ are identical or different and are hydrogen,
(C6-Cl2)-arYl~ ~Cl-C1O)-alkyl, (c3-clo)-cycloalkyl~
(C1-C8)-alkoxy-(C1-C8)-alkyl, (C7-C12)-aralkoxy-(C1-
C8) alkyl, ~C6-C12)-aryloxy-(C1-C8)-alkyl, (C1-C10)-
alkanoyl, optionally substituted (C7-C16)-
aralkanoyl, or optionally substituted (C6-C12)-
aroyl, or
RY and RZ together are -tCH2]h-, wherein one CH group can
be replaced by O, S, N-(C1-C4)-alkanoylimino or
N-(C1-C4)-alkoxycarbonylimino,
m is o or 1,
f is 1 to 8,
g is 0 or 1 to (2f + 1),
h is 3 to 6 and5 x is 0 to 3, including the physiologically active
salts.
Particularly preferred compounds of the formula I are
those in which
m is 0,0 A is a -CH2- group, which can be substituted by a
methyl group,
B is -CO2H,
R1 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, chlorine
or bromine,
Rs is hydrogen, fluorine, chlorine or methyl and
R2, R3 and R4 are identical or different and are hydro-
gen, (C1-C18)-alkyl~ (C2-C18)-alkenyl, (C2-C1g)-
alkynyl, phenyl, chlorine, fluorine, bromine,
hydroxyl, trifluoromethyl, ~C1-C18)-alkylsulfinyl,
(C1-C18)-alkylsulfonyl, phenylsulfinyl, phenyl-
sulfonyl, naphthylsulfinyl, naphthylsulfonyl,
(Cl-C18)-alkoxy, (C3-C8)-cycloalkoxy, ~Cl-C8)-alkoxy-
(C1-C8)-alkoxy, -O-tCH2]X-cfH(2f+l-g)Fg~ phenyl-
~C1-C4)-alkoxy, phenoxy, (C1-C12)-alkanoyl, phenyl-
(C1-C4)-alkanoyl or benzoyl, where, in substituents
with a phenyl or naphthyl ring, this optionally

- 2 1 867 1 7
carries up to 5 identical or different substituents
from the series comprising fluorine, chlorine,
bromine, nitrile, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -O~tCH2]x~CfH(2f+1_g)Fg or (C1-C6~-
alkylsulfonyl,
including the physiologically active salts.
E~pecially preferred compounds of the formula I are thosein which
m is 0,
A is a -CH2- group,
B is -CO2H,
R1 and R5 are hydrogen and
R2, R3 and R4 are identical or different and are hydro-
gen, (C1-C18)-alkyl, (C1-C18)-alkenyl, phenyl, chlor-
ine, fluorine, bromine, trifluoromethyl, (C1-C18)-
alkylsulfinyl, (C1-Cl8)-alkylsulfonyl, phenyl-
sulfinyl, phenylsulfonyl, naphthylsulfinyl,
naphthylsulfonyl, (Cl-C18)-alkoxy, (C3-C8)-cyclo-
alkoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy, -O-[CH2]X-
C~H(2f+1-g)Fs~ phenyl-(C1-C4)-alkoxy, phenoxy,
(C1-C12)-alkanoyl, phenyl-(C1-C4)-alkanoyl or
benzoyl, where, in substituents having a phenyl or
naphthyl ring, this optionally carries up to 5
identical or different substituents from the series
comprising fluorine, chlorine, bromine, nitrile,
trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,
~O~~CH2]X~CfH(2f+l_g)Fg and (C1-C6)-alkylsulfonyl,
including the physiologically active salts.
Particularly preferred compounds of the formula I are
those in which
m is 0,
A is a -CH2- group,
R1 and R5 are hydrogen,
one of the substituents R2, R3 or R4 is hydrogen and the
other two are identical or different and are hydrogen,
(C1-C16)-alkyl, fluorine, chlorine, bromine, trifluoro-
methyl, (C1-C16)-alkylsulfonyl, phenylsulfonyl, (C1-C16)-

2186717
- 18 -
alkoxy, (cl-c8)-alkoxy-(cl-c8)-alkoxy~ -o-tcH2]x-
CfH(2f+1g)Fg, benzyloxy or phenoxy, where, in substituents
which contain a phenyl ring, this optionally carries up
to 3 substituents from the series comprising fluorine,
chlorine, bromine, trifluoromethyl, (C1-C6)-alkyl,
(C1-C6)-alkoxy, -o-tcH2]x-cfH(2f+l-g) Fg or (c1-C4)-alkyl-
sulfonyl, including the physiologically active salts.
Particularly preferred compounds of the formula I are
those in which
m is 0,
A is a -CH2- group,
R1, R2 and R5 are hydrogen and
R3 and R4 are identical or different and are hydrogen,
(C1-C16)-alkyl, fluorine, chlorine, trifluoromethyl,
lS (C1-C16)-alkylsulfonyl, phenylsulfonyl, naphthylsulfonyl,
(C1-C16)-alkoxy, (C1-C8)-alkoxy-(C1-C8)-alkoxy, 0 tCH2]X
CfH(2f+1_g)Fg, benzyloxy or phenoxy, where, in substituents
which contain a phenyl ring, this optionally carries up
to 3 substituents from the series comprising fluorine,
chlorine, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy,
tCH2]x~CfH(2f+1_g)Fg and (C1-C4)-alkylsulfonyl, including
the physiologically active salts.
Particularly preferred compounds of the formula I are
furthermore those in which
m is 0,
A is a -CH2- group,
R1, R2, R3 and R5 are hydrogen and
R4 is hydrogen, (C1-C12)-alkyl, fluorine, chlorine,
bromine, trifluoromethyl, ~C1-C12)-alkylsulfonyl, phenyl-
sulfonyl, naphthylsulfonyl, (C1-C12)-alkoxy, ~C1-C6)-
alkoxy-(C1-C6)-alkoxy, ~0~tCH2]x~CfH(2f+1_g)Fg~ benzyloxy or
phenoxy, where, in substituents which contain a phenyl or
naphthyl ring, this is optionally monosubstituted by
fluorine, chlorine, bromine, trifluoromethyl, ~C1-C6)-
alkyl, (C1-C6)-alkoxy, ~O~[CH2]x~CfH(2f+l g)Fg or ~C1-C4)-
alkylsulfonyl, including the physiologically active
salts.

21 i8~7~ 7
-- 19 --
Particularly preferred compounds of the formula I are, in
addition, those in which
m is 0,
A is a -CH2- group,
Rl, R3, R4 and R5 are hydrogen and
R2 is hydrogen, ~C1-C12)-alkyl, fluorine, chlorine,
bromine, trifluoromethyl, (C1-C12)-alkylsulfonyl, phenyl-
sulfonyl, naphthylsulfonyl, (C1-C12)-alkoxy, (C1-C6)-
alkoxy-(C1-C6)-alkoxy, ~O~[CH2]X~CfH(2f+l_g)Fg, benzyloxy or
phenoxy, where, in substituents which contain a phenyl or
naphthyl ring, this is optionally monosubstituted by
fluorine, chlorine, bromine, trifluoromethyl, (C1-C6)-
alkyl, (C1-C6)-alkoxy~ -0-tCH2]x-cfH(2f+l-g)Fg or (Cl-C4)-
alkylsulfonyl, including the physiologically active
salts.
Particularly preferred compounds of the formula I are
furthermore those in which
m is 0,
A is a -CH2- group,
R1, R2 and R5 are hydrogen,
R4 is hydrogen or chlorine and
R3 is hydrogen, fluorine, chlorine, (C1-C12)-alkoxy,
(Cl~c4)~alkOxy-(cl-c6)-alkoxy~_o-[cH2]x-
CfH(2f+1g)Fg, phenylsulfonyl, naphthylsulfonyl or
phenoxy, where, in substituents which contain a
phenyl or naphthyl ring, this optionally carries up
to 3 identical or different substituents, preferably
one substituent, from the series comprising
fluorine, chlorine, bromine, trifluoromethyl,
trifluoromethoxy, (C1-C6)-alkyl and (C1-C6)-alkoxy,
including the physiologically active salts.
Particularly preferred compounds are furthermore those of
the formula I in which
m is 0,
A is a -CH2- group,
Rl, R2, R4 and R5 are hydrogen and
R3 is hydrogen, fluorine, chlorine, (C1-C12)-alkoxy,

2186717
- 20 -
(C1-C4)-alkoxy-(C1-C6)-alkoxy, -O-[CH2]X-CfH(2f+1-g)Fg,
phenylsulfonyl, naphthylsulfonyl or phenoxy, where,
in substituents which contain a phenyl or naphthyl
ring, this optionally carries up to 3 identical or
different substituents, preferably one substituent,
from the series comprising fluorine, chlorine,
bromine, trifluoromethyl, trifluoromethoxy, (C1-C6)-
alkyl and (C1-C6)-alkoxy, including the physiologi-
cally active salts.
The invention furthermore relates to prodrugs to the
compounds of the formula (I) which have the effect of
inhibiting collagen biosynthesis in vivo owing to
liberation of compounds of the formula I or salts
thereof.
Finally, the invention also relates to prodrugs which
have the effect of inhibiting prolyl 4-hydroxylase in
vivo owing to liberation of compounds of the formula I or
salts thereof.
Prodrug groupings are chemical groups which, in vivo,
0 - can be converted into the carboxylate group of the
compounds of the formula I and/or
- can be split off from the amide N atom and/or
- can be converted into a quinoline ring.
The prodrug groups possible are known to the expert.
The following prodrug groupings are mentioned in particu-
lar:
for the carboxylate group ester, amide, hydroxymethyl and
aldehyde groups and derivatives thereof, and for the
guinoline N atom N-oxides and N-alkyl derivatives.
The invention relates to the use of compounds of the
formula I and the physiologically tolerated salts for
inhibition of collagen biosynthesis.

2i86717
- 21 -
The invention relates to the use of compounds of the
general formula I and the physiologically tolerated salts
for inhibition of prolyl 4-hydroxylase.
The invention furthermore relates to the use of compounds
of the formula I and the physiologically tolerated salts
for the preparation of a pharmaceutical (medicament)
against fibrotic diseases.
The invention furthermore relates to the use of compounds
of the formula I and the physiologically tolerated salts
for the preparation of a medicament against fibrotic
diseases of the liver, the lungs and the skin.
Finally, the invention relates to the compounds of the
formula I for use as medicaments.
The invention particularly relates to the compounds of
the formula I for use as fibrosuppressants.
The invention furthermore relates to a process for the
preparation of compounds of the formula I.
The compounds of the formula I in which
A - B is -(CH2)1_4-CO2H and
m is O are prepared by
l.il.) reacting quinoline-2-carboxylic acids of the
formula II (Rl1 = H) with the amino esters of the
formula III to give the amide esters of the
formula IV, or
5 l.i2.) reacting quinoline-2-carboxylic acid esters of
the formula II (R11 = lower alkyl) under the
conditions of aminolysis to give the compounds of
the formula IV;

2186717
l.ii) liberating the compounds of the formulae I and V
from the esters of the formulae IV and VI; and
l.iii) obtaining the compounds of the formulae I and VI
from the compounds of the formulae V and IV by
splitting off the hydroxyl-protective group R10,
and if appropriate
l.iv) oxidizing the compounds of the formula I, IV, V
or VI to give compounds of the formulae Ia, IVa,
Va or VIa.
Suitable protecting groups (PG = Protecting Groups) such
as are familiar to the expert are, in particular, benzyl,
p-methoxybenzyl, 3,4-dimethoxybenzyl, alkyl, methoxy-
methyl ~MOM), methylthio, benzyloxymethyl (BOM),
t-butyloxymethyl, 2-methoxyethoxymethyl ~MEM) and
tetrahydropyranyl (THP).
Further protecting groups and the conditions under which
they are split off (conversion of compounds of the
formula V into compounds of the formula I) are described
by Theodoro W. Greene, Peter G.M. Wuts, in Protective
Groups in organic Synthesis, Second Edition 1991, John
Wiley, Chapter 2 and 3, pages 10 to 174.
Equation 1.1. R10 = PG (Protecting Group)
A - B = (CH2)1_4-CO2H

2 1 8~
- 23 -
A-B = (CH2)l.4-C02H
R 2 R R R
R~OR H2N-A-co2R R~ OR lo
R~N CO~R 111 R~`N~NH-A-CO2R
R 1 i2 1 IV 1.iv.)
1 iii~ IVa
~ 1.ii) ,
R R R R
R~OR R~OH
R~N~NH-A-C02H RJ~N~NH-A-co2R
R O R O
V Vl
1 .iv )
\\~ / l.ii) Vla
Va R R
R ~ O H
R~--N~NH-A-COzH
R O
Ib
1.iv) j
R R
R~ ~OH
R~N~NH-A-CO2H
R O O
la
Rll = H, (Cl-C8)-alkyl or benzyl
R12 = H, (Cl-C8)-alkyl or benzyl
If the 3-OH function in the quinoline-2-carboxylic acids
of the formula II a is present without a protecting
group, these compounds can be reacted directly with the
amino acid esters of the formula III to give the com-
pounds of the formula VI.

21~67~7
Equation 1.2., R10 = H
R2 Rl
R~"OH H2N--A C02R12
R~N CO2H ' Vl
R i.1.)
lla
To prepare the quinoline N-oxides of the formula I
~= Ia), the compounds of the formulae I, IV, V or VI are
converted into their corresponding N-oxides of the
formulae Ia, IVa, Va or VIa, and these are further
treated analogously to equation 1.1.
æuitable processes for amide formation (reaction l.il.)
are the methods of carboxyl activation and the condensa-
tion reactions known from peptide chemistry.
Reagents which can be used for activation of the carboxy-
lic acids are the substances known to the expert, such as
thionyl chloride, oxalyl chloride, pivaloyl chloride,
chloroformic acid ester derivatives or N,N'-
carbonyldiimidazole. The activated derivatives of the
compounds of the formula II are reacted in situ, after
their preparation, with the amide derivatives of the
formula III.
A suitable condensing agent is, for example, the combina-
tion of N,N'-dicyclohexylcarbodiimide, 1-hydroxy-lH-
benzotriazole and N-ethylmorpholine.
Suitable solvents are methylene chloride, carbon
tetrachloride, butyl acetate, ethyl acetate, toluene,
tetrahydrofuran, dimethoxyethane, 1,4-dioxane,
acetonitrile, N,N-dimethylformamide, N,N-dimethyl-
acetamide, dimethylsulfoxide, nitromethane and/or

218~717
- 25 -
pyridine.
To prepare the compounds of the formula II, appropriately
substituted quinolines having a protected hydroxyl
function in the 3-position and an oxidizable group G in
the 2-position are subjected to oxidation reactions
~equation 2.1.).
Equstion 2.1., G = oxidizable group, for example CH3,
CHO, CH2OH or CO-CH3
~ ' OR Oxidation ~f OR
R~N G R~N CO2H
R5 R
Vll 11 c
Variously substituted 3-hydroxy derivatives of the
quinoline-2-carboxylic acids of the formula II are
obtained in accordance with equation 2.2.
2.i) Substituted 2-nitrobenzoic acids of the for-
mula VIII are treated by the customary methods of
carboxylic acid activation and reacted with salts
of acetylacetone to give the compounds of the
formula IX.
2.ii) The compounds of the formula IX are cyclized with
a base to give the 2-acetyl-3-hydroxyquinolines
of the formulae Xa/b.
0 2.iii) The compounds of the formula Xa are reacted with
a reagent R10-X to give the hydroxyl-protected
compounds of the formula XI.
2.iv) The compounds of the formula XI are oxidized to

2~86717
- 26 -
give the compounds of the formula II, preferably
under the conditions of the haloform reaction.
Equation 2.2. R1 = H, R10 = PG ~Protecting Group)
R R OH O
R ~ COzH1. Carboxylic acid R
R~No2 Activation R~NO
Vlll ~
2. IX
Base
2.ii) Base/aqueous
Medium
O~C-1 OO~C
R H R H
R~OR 2.iii) R~,~OH
R ~ N'--f OBa~se X R ~ Y'~CHO
R C H
Xl
Haloform X
Oxidation Xa m=0
Xb m= 1
2.iv)
R H ~O X Auxiliarygroup
R ~ J~, O R for introduction of
Il T T the protecting group
R ~ N CO H R', for exarnple
IIb
The preparation of 3-(2-nitrobenzoyl)acetylacetone
~formula IX; R2-R5 = H) is known, J. Prakt. Chem. 1987,
329, page 1063.
The reaction of the compounds of the formula IX with
aqueous potassium hydroxide solution to give the com-
pounds of the formula Xa in which R2, R4 and R5 are
hydrogen and R3 is hydrogen, methyl or chlorine is known
from G. Tennant et al., J. Chem. Soc. Chem. Comm. 1975,
782.

21~7a 7
It has now been found that the substituents R2, R3, R4 and
R5 can be varied according to the invention to achieve
the object described.
It has furthermore been found that the compounds of the
formula XI can be oxidized in a mild manner under the
conditions of the haloform reaction (aqueous alkali metal
or alkaline earth metal hydroxide/bromine) to give the
compounds of the formula II (IIb).
2-Nitrobenzoic acids of the formula VIII are commercially
obtainable or known from the literature, or can be
prepared by various synthesis methods - depending on the
desired substitution pattern.
The compounds of the formulae II, IIa and IIb (intermedi-
ate products) are novel, with the following exceptions:
Compounds of the formula II in which - if R1 to R5 and R
are hydrogen - R10 is benzyl or methyl,
(or compounds of the formula IIb in which - if R2 to R5
are hydrogen - R10 is benzyl or methyl) and
compounds of the formula II in which - if R1 to R5 are
hydrogen and R11 is ethyl - R10 is hydrogen, benzyl or
p-toluenesulfonyl and
compounds of the formula IIa in which - if R1, R2, R4 and
R5 are hydrogen - R3 is hydrogen or methoxy.
3-Benzyloxyquinoline-2-carboxylic acid is known from
J. Am. Chem. Soc., Volume 115, No. 24, 1993, pages 11624-
11625.
3-Hydroxyquinoline-2-carboxylic acid and methyl 3-
methoxyquinoline-2-carboxylate are described in
J. Antibiot. 1987, 40 (7), pages 953-960, and the former
is also described in Chem. Pharm. Bull. 1967, 15 (5),
pages 663-669.

218~7~7
- 28 -
3-Hydroxy-6-methoxyquinoline-2-carboxylic acid is
described in J. Am. Chem. Soc., Vol. 103, No. 5, 1981,
pages 1241 - 1243.
3-Methoxyquinoline-2-carboxylic acid is known from J. Am.
Chem. Soc. 1960, pages 3371-3377.
Ethyl 3-hydroxyquinoline-2-carboxylate and ethyl 3-(p-
toluenesulfonyloxy)quinoline-2-carboxylate are known from
J. Chem. Soc. C. 1967, 4, pages 256-261.
Intermediate products of the formulae Xa and Xb are
furthermore novel, with the following exceptions:
Compounds of the formula Xa in which - if R2, R4 and R5
are hydrogen - R3 is hydrogen, methyl or chlorine. These
known compounds of the formula Xa are described in J.
Chem. Soc. Chem. Comm. 1975, pages 782 to 783.
The invention therefore also relates to the following
intermediate products for the preparation of the com-
pounds of the formula I:
Intermediate products of the formula II in which Rl to R5
have the meanings which apply to the compounds of the
formula I,
R10 is H or an HO-protecting group (Protecting Group PG)
and
R11 is hydrogen, (C1-C8)-alkyl or benzyl,
with the exception of compounds of the formula II in
which R10 is benzyl or methyl if Rl to R5 and Rll are
hydrogen, and those compounds from the formula II in
which Rl is hydrogen, benzyl or p-toluenesulfonyl if
to R5 are hydrogen and Rll is ethyl.
Intermediate products of the formula Xa in which R2 to R5
have the meanings which apply to the compounds of the
formula I,
with the exception of compounds of the formula Xa in
which R3 is hydrogen, methyl or chlorine if R2, R4 and R5
are hydrogen.

2 1 8~7~ ~
- 29 -
Alkoxy- and benzyloxy-substituted quinoline systems of
the present invention are prepared by alkylation of
phenolic OH group(s) of 2-nitrobenzoic acids or deriva-
tives thereof in which, after alkylation, the carboxylate
group is introduced by oxidation of methyl, acetyl,
hydroxymethyl or aldehyde groups or obtained by hydroly-
sis of an ester group, cf., for example, equation 3.1.
Equation 3.1.
H~ R-X1 OH Oxidation \~CO H
Xll Xlll XIV
X1 = Hal, tosylate or mesylate
R = (C1-C12)-alkyl, benzyl or (C1-C6)-alkoxy-(C1-C6)alkyl
6-Aryloxyquinoline and 6-arylsulfonyl derivatives are
accessible by nucleophilic aromatic substitution on
4-halo-2-nitrotoluenes XV and subsequent oxidation to
give the corresponding 5-aryloxy (5-arylsulfonyl)-2-
nitrobenzoic acids XVII, cf. equation 3.2..
Equation 3.2.
X~ NO2 Base ~ ~ OxidaUon ~CO ~H
XV XVI XVI I
x2 = F, Cl, 0502CF3 Y = O, SZ = SO2
Another possibility is provided by nitration of appropri-
ately substituted toluenes, benzoic acids, benzaldehydes

- 2 1 ~
- 30 -
or acetophenones. This method is preferably used if the
substituents present direct the nitration exclusively or
predominantly into the 2 position, cf., for example,
equation 3.3..
Equation 3.3.
R `13~ C 0 2H R ~ C 2 H
XVII XIX
R3 = -[CH2]XcfF(2f+1-9)F9
The compounds of the formula XIII and XVI were reacted
with an oxidizing agent, preferably with RMnO4 in an
aqueous alkaline medium, to give the 2-nitrobenzoic acid
derivatives.
The compounds of the formula I are inhibitors of prolyl
4-hydroxylase. The inhibition of this enzyme was
determined as described by Kaule and Gunzler in Annal.
Biochem. 184, 291 to 297 (1990).
The compounds of the formula I according to the invention
furthermore have valuable pharmacological properties and
show, in particular, an antifibrotic activity.
The antifibrotic action can be determined in the model of
fibrosis of the liver induced by carbon tetrachloride.
For this, rats are treated twice weekly with CCl4
(1 ml/kg), dissolved in olive oil. The test substance is
administered daily, if appropriate even twice daily,
perorally or intraperitoneally - dissolved in a suitable
tolerated solvent. The extent of the fibrosis of the
liver is determined histologically and the content of

21867~7
collagen in the liver is analyzed by hydroxyproline
determination - as described by Kivirikko et al. (Anal.
Biochem. 19, 249 et seq. (1967)). The activity of the
fibrogenesis can be determined by radioimmunological
determination of collagen fragments and procollagen
peptides in the serum. The compounds according to the
invention are active in this model in a concentration of
1 to 100 mg/kg.
The activity of the fibrogenesis can be determined by
radioimmunological assay of the N-terminal propeptide of
type III collagen or of the N- or C-terminal crosslinking
domain of type IV collagen (7s collagen or type IV
collagen NC1) in the serum.
For this purpose, the hydroxyproline, procollagen III
peptide, 7s collagen and type IV collagen NC concentra-
tions in the liver of
a) untreated rats (control)
b) rats to which carbon tetrachloride was administered
( CC 14 control)0 c) rats to which first CCl4 and then a compound accord-
ing to the invention was administered
were measured (this test method is described by
Rouiller, C., experimental toxic injury of the liver; in
The Liver, C. Rouiller, Volume 2, 5. 335 to 476, New
York, Academic Press, 1964).
An activity of the compounds according to the invention
can furthermore be detected in the following systems.
Inhibition of hepatic prolyl 4-hydroxylase in vivo:
This model is used for detection of acute inhibition of
prolyl 4-hydroxylase in vivo. For this, the test sub-
stance and the corresponding vehicle are administered
(intraperitoneally, intravenously, perorally) to rats of
both sexes (healthy and with induced fibrosis of the
liver) and, after administration of the substance, 14C-L-

2 1 867 1 7
- 32 -
proline (250 ~Ci/kg of body weight) is administered
intraperitoneally. 14C-L-Proline ~250 ~Ci/kg of body
weight) is then administered again intraperitoneally.
Finally, the animals are exsanguinated under pento-
barbital anesthesia and the liver is removed. The hepaticcollagen was purified by pepsin digestion and fractional
ammonium sulfate precipitation in accordance with pub-
lished protocols (Ref. 1, 2). The purified liver collagen
was hydrolyzed and the content of 14C-hydroxyproline and
14C-proline was determined by amino acid analysis by
means of ion exchange chromatography. Inhibition of
prolyl 4-hydroxylase can be seen from a reduction in the
quotient 14C-hydroxyproline/t C-hydroxypro~ine +
14C-proline]. 2,2'-Dipyridyl is used as the reference
substance. (Ref. 1: Chojkier, M. 1986. Hepatocyte col-
lagen production in vivo in normal rats. J. Clin. Invest.
78: 333-339 and Ref. 2: Ogata I. et al. 1991. Minor con-
tribution of hepatocytes to collagen production in normal
and early fibrotic livers. Hepatology 14: 361-367).
Inhibition of prolyl 4-hydroxylase in cell cultures:
The following cell types are used for testing prolyl
4-hydroxylase inhibitors in cell cultures:
Normal human dermal fibroblasts (NHDF), rat liver
epithelial cells (Ref. 1) and primary fat storing cells
from the rat liver (Ref. 2). For this, the cells are
cultured in the presence of inhibitors. At the same time,
the collagen newly synthesized during this period is
labeled metabolically by 4-3H-L-proline and 14C-proline.
The influence of the test substances on the degree of
hydroxlyation of the collagen is then determined in
accordance with the method of Chojkier et al. (Ref. 3).
2,2'-Dipyridyl is employed as the reference substance.
(1.: Schrode, W., Mecke, D., Gebhard, R. 1990. Induction
of glutamine synthetase in periportal hepatocytes by co-
cultivation with a liver epithelial cell line. Eur. J.Cell. Biol. 53: 35-41, 2. Blomhoff, R., Berg T. 1990.
Isolation and cultivation of rat liver stellate cells.

- 2186717
- 33 -
Methods Enzymol. 190: 59-71 and 3.: Chojkier, M.
Peterkofsky, B. Bateman J. 1980. A new method for
determining the extent of proline hydroxylation by
measuring changes in the ration of t4-3H] [14C] proline in
collagenase digests. Anal. Biochem. 108: 385-393).
The compounds of the formula I can be used as medicaments
in the form of pharmaceutical preparations which comprise
them, if appropriate with tolerated pharmaceutical
excipients. The compounds can be used as medicines, for
example in the form of pharmaceutical preparations, which
comprise these compounds as a mixture with a pharmaceuti-
cal, organic or inorganic excipient suitable for enteral,
percutaneous or parenteral administration, such a~, for
example, water, gum arabic, gelatin, lactose, starch,
magnesium stearate, talc, vegetable oils, polyalkylene
glycols, petroleum jelly and the like.
For this purpose, they can be administered orally in
doses of 0.1 to 25 mg/kg/day, preferably 1 to 5 mg/kg/
day, or parenterally in doses of 0.01 to 5 mg/kg/day,
preferably 0.01 to 2.5 mg/kg/day, in particular 0.5 to
1.0 mg/kg/day. In severe cases, the dosage can also be
increased. However, lower doses are also sufficient in
many cases. These data relate to an adult weighing about
75 kg.
In the examples described below, the compounds of the
formula I according to the invention are understood as
meaning substituted quinoline-2-carboxylic acid N-
(carboxymethyl)amides (quinoline-2-carboxylic acid
glycinamides).
The term substituted N-((quinolin-2-yl)-carbonyl)-
glycines is used in parallel.
Example 1
3-Hydroxyquinoline-2-carboxylic acid N-(carboxymethyl)-
amide
a) 3-(2-Nitrobenzoyl)acetylacetone was obtained from

- 21B~7~ 7
- 34 -
acetylacetone and 2-nitrobenzoyl chloride, melting point
69C; cf. J. Prakt. Chem. 1987, 329, page 1063, 29 %
yield.
b) 2-Acetyl-3-hydroxyquinoline was obtained from the
product a) under basic conditions (XOH/water, Smiles
rearrangement), melting point 105C; cf. J. Chem. Soc.
Chem. Comm. 1975, 782; 53 % yield.
c) 2-Acetyl-3-benzyloxyquinoline was obtained from the
product b) with benzyl bromide (potash/acetone), 52 %
yield.
H-NMR (CDCl3): ~ = 2.89 (2, 3 H), 5.25 (s, 2 H), 7.38
Im, 3 H), 7.58 (m, 5 H), 7.70 (m, 1 H), 8.08 (m, 1 H).
d) 3-Benzyloxyguinoline-2-carboxylic acid was obtained
from the product c) with potassium hypochlorite (dioxane/
water), oily crude product, 47 % yield,
H-NMR (CDCl3): ~ = 5.40 (s, 2 H), 7.40 (m, 3 H), 7.63
(m, 4 H), 7.75 (m, 2 H), 8.07 (m, 1 H).
e) 3-Benzyloxyquinoline-2-carboxylic acid N-((benzyl-
oxycarbonyl)methyl)amide was obtained from the product d)
with triethylamine/ethyl chloroformate (mixed anhydride
method) and glycine benzyl ester tosylate, oily crude
product, 64 % yield,
H-NMR (CDCl3): ~ = 4.40 (d, 2 H), 5.25 (s, 2 H), 5.35
(s, 2 H), 7.10 to 7.75 (m, 14 H), 8.10 (m, lH), 7.28
(t, 1 H).
f) The title compound was obtained by hydrogenating the
product e) in methanol with Pd/C (10 %) in a duck-shaped
shaking vessel, melting point 191C (from aqueous hydro-
chloric acid), 40 % yield.
Example 2
N-((3-Hydroxy-6-methoxyquinolin-2-yl)carbonyl)glycine
a) 3-~5-Methoxy-2-nitrobenzoyl) acetylacetone

- 2~6~
28 g of crude product was obtained from 19.75 g of
5-methoxy-2-nitrobenzoic acid with oxalyl chloride and Mg
acetylacetonide analogously to Example 4c).
b) 2-Acetyl-3-hydroxy-6-methylquinoline
28 g (0.1 mol) of the above crude product were heated
under reflux in 250 ml of 20 % strength aqueous KOH
solution for 30 minutes. The mixture was worked up as
under Example 4d), the crude product was chromatographed
over silica gel with n-heptane/ethyl acetate ~1:1) and
5.1 g of product was crystallized from corresponding
fractions with diisopropyl ether, melting point 124-
126C.
c) 2-Acetyl-3-benzyloxy-6-methoxyquinoline, from the
~bove compound by alkylation with benzyl bromide, melting
point 100-102C (from diisopropyl ether).
d) 3-Benzyloxy-6-methoxyquinoline-2-carboxylic acid
1.2 g (4 mmol) of the above acetyl compound, dissolved in
5 ml of 1,4-dioxane, were added dropwise to a solution of
1.6 g of NaOH (40 mmol) in 8 ml of water, to which 0.6 ml
(12 mmol) of bromine had been added at 5-10C. After a
little diethyl ether had been added and the organic phase
had been separated off, a solution of 0.4 g of sodium
disulfite in 6 ml of water was added to the alkaline
solution, the mixture was concentrated in vacuo, the
residue was taken up in 8 ml of water, the pH was brought
to 2 with concentrated HCl, while cooling, and the
product which had crystallized was filtered off with
suction and dried, 0.83 g, melting point 272-275C
(sintering 90C).
e) N-((3-Benzyloxy-6-methoxyquinolin-2-yl)carbonyl)-
glycine 1-butyl ester
0.83 g (2.7 mmol) of the above carboxylic acid were

2~8~37
- 36 -
reacted with 0.82 g ~2.7 mmol) of glycine butyl ester
tosylate, 1.1 ml (8.1 mmol) of NEM, 0.405 g (3 mmol) of
HOBT and 1.14 g (2.7 mmol) of CMC in 200 ml of anhydrous
methylene chloride analogously to Example 4g). The crude
product was chromatographed over silica gel with ethyl
acetate. 0.8 g of product was crystallized from
corresponding fractions with diisopropyl ether, melting
point 90-92C.
f) N-(~3-Benzyloxy-6-methoxyquinolin-2-yl)carbonyl)-
glycine
0.5 g ~1.2 mmol) of the above ester was hydrolyzed in
1.5 N methanolic sodium hydroxide solution, 0.45 g of
product, melting point 118aC (sintering at 105C, from
aqueous hydrochloric acid).
g) The title compound was obtained by hydrogenating
0.4 g (1.1 mmol) of the above benzyl compound in meth-
anol/tetrahydrofuran (1:1) with Pd/C (10 %) in a duck-
shaped shaking vessel. After the catalyst had been
filtered off with suction and the filtrate concentrated
in vacuo, the residue was crystallized with diethyl
ether, 0.16 g, melting point 258-260C.
Example 3
N-((6-(1-Hexyloxy)-3-hydroxyquinolin-2-yl)carbonyl)-
glycine
Example 4
N-((6-(1-Butyloxy)-3-hydroxyquinolin-2-yl)carbonyl)-
glycine
a) 5-(1-Butyloxy)-2-nitrobenzyl alcohol
5.1 g (30 mmol) of 5-hydroxy-2-nitrobenzyl alcohol were
stirred with 2.5 ~ (18 mmol) of potassium carbonate and
25 ml of N,N-dimethylacetamide at 70-80C for 30 min-
utes. After cooling to 20C, 3.9 ml ~36 mmol) of

21 8G711 1
1-butylbromide were added dropwise and the mixture was
stirred at 90C for 2 hours. After cooling, the reaction
mixture was concentrated in vacuo, the residue was
treated with water and the pH was brought to 7 with 2 N
HCl. The oil obtained crystallizes after about 30 min-
utes; the product was filtered off with suction, washed
with water and dried; 6 g, melting point 47-49C.
b) 5-(1-Butyloxy)-2-nitrobenzoic acid
0.5 g ~10 mmol) of potassium hydroxide was dissolved in
40 ml of water, 2.2 g (10 mmol) of the above alcohol were
added at 20C, while stirring, the mixture was heated to
70-80C and 3.16 g (20 mmol) of potassium permanganate
were added in portions. Af ter the mixture had been
~tirred at 60-70C for 30 minutes, it was filtered hot
with suction, the residue on the f ilter was washed with
hot water, the filtrate was concentrated to 20 ml and
half-concentrated hydrochloric acid was added down to a
pH of 1-2. The oil which separates off crystallized after
1 hour. The product was filtered off with suction and
washed with water, 2 g, melting point 82-84C.
c) 3-(5-(1-Butyloxy)-2-nitrobenzoyl)acetylacetone
1. 5-(1-Butyloxy)-2-nitrobenzoyl chloride
3 drops of N,N-dimethylformamide and, dropwise, 7 ml of
oxalyl chloride (in 12 ml of tetrahydrofuran) were added
to 12 g (50 mmol) of the above benzoic acid in 90 ml of
anhydrous tetrahydrofuran at 5C.
The mixture was allowed to warm to room temperature and
was stirred for 1 hour and concentrated in vacuo, and the
residue was taken up in 25 ml of anhydrous toluene.
2. Magnesium acetylacetonide
1.23 g (50 mmol) of magnesium chips were heated under
reflux with a crystal of iodine in 20 ml of anhydrous
ethanol and 2.5 ml of xylene for 8 hours. The mixture was
then concentrated in vacuo, the residue was taken up in

2 ~ 7
-
-- 38 --
100 ml of anhydrous toluene, 5.2 ml (So mmol) of freshly
distilled acetylacetone were added dropwise at 20C and
the mixture was stirred for 30 minutes.
This solution of magnesium acetylacetonide in toluene was
5 cooled to 0C and the solution, prepared under 1., of the
acid chloride was added dropwise, while stirring. The
mixture was stirred at oC for 1 hour and left to stand
overnight at 20C, 200 ml of ice-water and concentrated
hydrochloric acid to pH 1 were added, the mixture was
10 stirred for 30 minutes and the organic phase was washed
with water and dried to give, after concentration in
vacuo, 14 g of oily crude product.
d) 2-Acetyl-6-(1-butyloxy)-3-hydroxyquinoline
14 g ~43.6 mmol) of the above product were heated under
reflux in 150 ml of 20 % strength aqueous KOH solution
for 30 minutes. After cooling, the pH was brought to 1-2
with half-concentrated hydrochloric acid, while stirring,
the mixture was extracted three times with methylene
chloride, the organic phase was dried and concentrated in
20 vacuo and the residue was chromatographed over silica gel
with n-heptane/ethyl acetate ~3:1). 2.5 g of product were
crystallized from corresponding fractions with petroleum
ether, melting point 71-73C.
e) 2-Acetyl-3-benzyloxy-6-(1-butyloxy)quinoline
25 2.5 g (about 10 mmol) of the above~ product were reacted
with 1.38 g (10 mmol) of potassium carbonate and 1.2 ml
~10 mmol) of benzyl bromide in 30 ml of N,N-dimethyl-
acetamide ~1 hour at 75-80C). 2.2 g of product were
obtained, melting point 91-93C (from diisopropyl ether).
30 f) 3-Benzyloxy-6-~1-butyloxy)quinoline-2-carboxylic
acid (haloform oxidation)
0.45 ml ~9 mmol) of bromine was added to a solution of

2186737
- 39 -
1.2 g (30 mmol) of NaOH in 6 ml of water at 5-10C, while
stirring. A solution of 1.05 g (3 mmol) of the above
acetyl compound, dissolved in 5 ml of 1,4-dioxane, was
then added dropwise. The mixture was stirrsd at 20C for
a further hour and extracted with 5 ml of diethyl ether,
the organic phase was concentrated, the residue was
treated with 2 N aqueous HCl, the mixture was decanted,
the residue was dissolved in ethyl acetate, the solution
was dried with magnesium sulfate and concentrated and the
residue was crystallized with diisopropyl ether. 0.8 g
was obtained, melting point 108-110C.
g) N-((3-Benzyloxy-6-(1-butyloxy)quinolin-2-yl)-
carbonyl)glycine 1-butyl ester
0.8 g (2.28 mmol) of the above quinoline-2-carboxylic
acid was dissolved in 200 ml of anhydrous methylene
chloride, 0.74 g (2.43 mmol) of glycine l-butyl ester
tosylate, 1.1 ml (8.1 mmol) of N-ethylmorpholine (NEM),
0.405 g (3 mmol) of l-hydroxybenzotriazole (HOBT) and
1.0 g (2.43 mmol) of N-cyclohexyl-N'-(2-morpholino-
ethyl)carbodiimide-methyl-p-toluenesulfonate (CMC) were
added in succession and the mixture was stirred at 20C
for 30 hours.
The reaction solution was then shaken with 2 N aqueous
HCl, dilute NaOH was added to a precipitate, the mixture
was extracted with diethyl ether, the combined organic
phases were extracted with aqueous Na bicarbonate sol-
ution, dried and concentrated and the residue was
chromatographed over silica gel with n-heptane/ethyl
acetate (2:1). After corresponding fractions had been
concentrated and treated with diisopropyl ether, 0.55 g
of product was obtained, melting point 99-101C.
h) The title compound was obtained by hydrolyzing 0.5 g
of the above glycine ester with 50 ml of 1 N methanolic
NaOH at 20C. The mixture was concentrated in vacuo,
water was added to the residue, the mixture was extracted

2~8~7~
-- 40 --
with diethyl ether, the aqueous, oily phase was acidified
after addition of tetrahydrofuran, while cooling, and
concentrated in vacuo, and the aqueous phase was
extracted with methylene chloride, dried and concentrated
5 to give 0.46 g of oily product. 0.3 g of the glycine
obtained was dissolved in 75 ml of tetrahydrofuran, Pd/C
~10 %) was added and the glycine was hydrogenated in a
duck-shaped shaking vessel. The catalyst was filtered off
with suction, the filtrate was concentrated and the
10 residue was crystallized with diisopropyl ether. 140 mg
of the title compound were obtained as a colorless
crystalline substance, melting point 180-182C.
Example 5
N-~6-Ethyloxy-3-hydroxyquinolin-2-yl)carbonyl)glycine
15 Example 6
N-~3-Hydroxy-6-~1-octyloxy)quinolin-2-yl)carbonyl)-
glycine
The title compound was obtained analogously to Example 4:
a) 2-Nitro-5-~1-octyloxy)benzyl alcohol
20 The oil obtained after treatment with 1 N hydrochloric
acid slowly crystallized completely, melting point 55-
57C
b) 2-Nitro-5-~1-octyloxy)benzoic acid, oily crude
product.
25 c) 3-~2-Nitro-5-~1-octyloxy)benzoyl)acetylacetone; oily
product ~after chromatography over silica gel with
n-heptane/ethyl acetate (3:1)).
d) 2-Acetyl-3-hydroxy-6-(1-octyloxy)quinoline, oily
product, which solidifies on standing.
30 e) 2-Acetyl-3-benzyloxy-6-~1-octyloxy)quinoline; oily
product which crystallized completely on standing.

21867~7
-- 41 --
f) 3-Benzyloxy-6-(1-octyloxy)quinoline-2-carboxylic
acid; melting point 145C (with decomposition, from
aqueous hydrochloric acid/tetrahydrofuran).
g) N-((3-Benzyloxy-6-(1-octyloxy) quinolin-2-yl) -
5 carbonyl)glycine benzyl ester; melting point 93-95C
(from petroleum ether).
h) The title compound was obtained by hydrogenating the
above benzyl compound with Pd/C; melting point 153-155C
(from petroleum ether).
10 Example 7
N-((6-(1-Decyloxy)-3-hydroquinolin-2-yl)carbonyl)glycine
Example 8
N-~(3-Hydroxy-6-((2,2,2-trifluoroethyl)oxy)quinolin-2-
yl)carbonyl)glycine hydrochloride
0.5 g (1.3 mmol) of N-((7-chloro-3-hydroxy-6-(2,2,2-
trifluoroethyloxy)quinolin-2-yl)carbonyl)glycine (title
compound from Example 31) was dissolved in 26 ml of
methanolic formic acid (4.4 % strength), and a further 26
ml of methanolic formic acid were added at 20C. After
20 addition of 0.5 g of Pd/C (10 %), the mixture was stirred
at 20C for 1 hour, the catalyst was filtered off, the
filtrate was concentrated and the residue was crystal-
lized with diisopropyl ether. 250 mg of product were
obtained, melting point > 300C (sintering at 207C).
25 Example 9
N-((3-Hydroxy-6-((2,2,3,3,3-pentafluoropropyl)oxy)-
quinolin-2-yl)carbonyl)glycine
Example 10
N-((6-((2,2,3,3,4,4,4-Heptafluorobutyl)oxy)-3-hydroxy-
30 quinolin-2-yl)carbonyl)glycine

2186717
.
- 42 -
Example 11
N-(~6-Chloro-3-hydroxyquinolin-2-yl)carbonyl)glycine
a) 2-Acetyl-6-chloro-3-hydroxyquinoline, cf. J. Chem.
8OC. Chem. Comm. 1975, 782.
b) 2-Acetyl-3-benzyloxy-6-chloroquinoline
5.0 g (22.5 mmol) of the above chloroquinoline were
dissolved in 50 ml of N,N-dimethylacetamide, the solution
was stirred with 3.4 g (25 mmol) of potassium carbonate
at 70-80C for 30 minutes, 3.1 ml (25 mmol) of benzyl
bromide were added dropwise at 20C and the mixture was
stirred at 90C for 2 hours. After working up, the
residue was chromatographed over silica gel with
n-heptane/ethyl acetate (4:1) and 4.2 g of product were
crystallized from corresponding fractions with di-
isopropyl ether, melting point 107-110C.
c) 3-Benzyloxy-6-chloroquinoline-2-carboxylic acid
2.1 g (6.7 mmol) of the above acetyl compound, dissolved
in 7 ml of 1,4-dioxane, were added dropwise to a solution
of 1 ml (20 mmol) of bromine in aqueous sodium hydroxide
solution (from 2.7 g (6.7 mmol) in 13.5 ml of water) at
0C. After working up, 1.2 g of product were obtained,
melting point 90-93C (sintering from 80C, from aqueous
hydrochloric acid).
d) N-((3-Benzyloxy-6-chloroquinolin-2-yl)carbonyl)-
glycine 1-butyl ester
The product was obtained analogously to Example 4g) from
1.1 g (3.3 mmol) of the above quinolinecarboxylic acid
and the coupling reagents NEM, HOBT, CMC and glycine
1-butyl ester tosylate, 0.75 g, melting point 121-123C
(from diisopropyl ether).
e) The title compound was obtained by hydrolyzing 0.3 g

2186717
- 43 -
(0.75 mmol) of the above glycine ester in 25 ml of 1 N
methanolic sodium hydroxide solution at 20C for 1 hour.
0.3 g of the resinous Na salt was isolated, 12.5 ml of
48 % strength aqueous HBr were added and the mixture was
stirred at a bath temperature of 80-85C for 1 hour.
After the mixture had been concentrated in vacuo, the
crystalline residue was extracted with tetrahydrofuran,
the extract was concentrated in vacuo and the residue was
crystallized with diisopropyl ether. 0.16 g of the title
compound was obtained, melting point 224C (with decompo-
sition).
Example 12
N-((6-Bromo-3-hydroxyquinolin-2-yl)carbonyl)glycine
Example 13
N-~(3-Hydroxy-6-(phenylsulfonyl)quinolin-2-yl)carbonyl)-
glycine
a) 2-Nitro-5-(phenylsulfonyl)toluene
4 g (100 mmol) of NaOH were dissoved in 150 ml of
anhydrous ethanol, while stirring and heating, 10.3 ml
(100 mmol) of thiophenol were added dropwise at 20C and,
after 10 minutes, 15.5 g (12.2 ml; 100 mmol) of 5-fluoro-
2-nitrotoluene, dissolved in 20 ml of ethanol, were added
dropwise. After 30 minutes at 20C, the mixture was
heated under reflux for 30 minutes and filtered hot.
After trituration, crystallization started. After addi-
tion of water, the product was filtered off with suction
and dried; 19 g of 2-nitro-5-phenylthiotoluene, melting
point 70-71C. Oxidation was then carried out with
m-chloroperbenzoic acid in methylene chloride; 20.5 g of
product, melting point 108-110C (from petroleum ether).
b) 2-Nitro-5-(phenylsulfonyl)benzoic acid
15 g (55 mmol) of 2-nitro-5-phenylsulfonyltoluene were
suspended in 210 ml of pyridine/water (1:2), and 79 g

2 1 8 6 7 1 7
(S00 mmol) of potassium permanganate were added in
portions, in each case until decoloration occurred, under
reflux. The mixture was then filtered hot with suction
and the residue was rinsed three times with hot water.
Starting material (2.8 g) which had precipitated out in
the filtrate was recovered. The second filtrate was
concentrated, 200 ml of water were added, the mixture was
extracted with diethyl ether and the aqueous phase was
brought to pH 1 with half-concentrated aqueous HCl, while
cooling. The product which had precipitated out was
filtered off with suction and dried; 9 g, melting point
210-212C.
c) 3-(2-Nitro-5-(phenylsulfonyl)benzoyl)acetylacetone
9.4 g of product were obtained from 9 g (30 mmol) of the
above substance with oxalyl chloride and magnesium
acetylacetonide analogously to Example 4c), melting point
143-145C (sintering at 140C, from diisopropyl ether).
d) 2-Acetyl-3-hydroxy-6-(phenylsulfonyl)quinoline
9.5 g of the above compound were introduced into 95 ml of
aqueous potassium hydroxide solution (20 % strength) at
20C, while stirring, a clear solution forming after
45 minutes. After 90 minutes, the pH was brought to 1
with half-concentrated HCl, while cooling, and the crude
product was filtered off with suction. This was chromato-
graphed over silica gel with n-heptane/ethyl acetate
(3:1). 1.5 g of product were isolated from corresponding
fractions, melting point 179-180C.
e) 2-Acetyl-3-benzyloxy-6-(phenylsulfonyl)quinoline
1.5 g (4.6 mmol) of the above compound were reacted with
0.63 g (4.6 mmol) of potassium carbonate and 0.55 ml (4.6
mmol) of benzyl bromide in 50 ml of diethyl ketone
(heating under reflux for 3 hours). 2.0 g of product were
obtained, melting point 160-162C (from water).

21857~7
-- 45 --
f) 3-Benzyloxy-6-(phenylsulfonyl)quinoline-2-carboxylic
acid
2.0 g (4.8 mmol) of the above acetyl compound were
subjected to the haloform reaction analogously to
S Example 4 f). 1.4 g of product, which was reacted fur-
ther, were obtained.
g) N-(~3-Benzyloxy-6-(phenylsulfonyl)quinolin-2-yl)-
carbonyl)glycine benzyl ester
1.4 g (3.3 mmol) of the above carboxylic acid were
10 reacted with glycine benzyl ester tosylate, N-ethyl-
morpholine, 1-hydroxy-lH-benzotriazole and CMC analogous-
ly to Example 4 g). 1.1 g of product were obtained,
melting point 165-167C (from diethyl ether).
h) The title compound was obtained by hydrogenating
15 1.1 g (1.9 mmol) of the above benzyl ester in tetrahydro-
furan with Pd/C (10 %) in a duck-shaped shaking vessel.
0.5 g of colorless product was obtained, melting point
196-198C (from diisopropyl ether).
Example 14
20 N-((6-~4-Fluorophenyl)sulfonyl)-3-hydroxyquinolin-2-
yl)carbonyl)glycine
Example 15
N-~(6-Benzyloxy-3-hydroxyquinolin-2-yl)carbonyl)glycine
Example 16
25 N-((6-(4-Fluorobenzyloxy)-3-hydroxyquinolin-2-yl) -
carbonyl)glycine
Example 17
N-((7-Butyloxy-3-hydroxyquinolin-2-yl)carbonyl)glycine
Example 18
30 N-((7-Benzyloxy-3-hydroxyquinolin-2-yl)carbonyl)glycine

218671 7
- 46 -
Example 19
N-~(6-(cis-3-Hexenyl-l-oxy)-3-hydroxyquinolin-2-yl)-
carbonyl)glycine
Example 20
N-((6-(trans-3-Hexenyl-1-oxy)-3-hydroxyquinolin-2-yl)-
carbonyl)glycine
Example 21
N-((3-Hydroxy-6-trifluoromethoxyquinolin-2-yl)carbonyl)-
glycine
a) 2-Nitro-5-trifluoromethoxybenzoic acid
29.7 ml of nitric acid were added dropwise to 76.5 ml of
concentrated sulfuric acid, while cooling and stirring,
and 9.0 g (43.7 mmol) of 3-trifluoromethoxybenzoic acid
were then added. The reaction mixture was heated at 50-
55C for 1 hour and, after cooling, was poured onto ice,and the residue was filtered off with suction to give,
after drying, 8.8 g of product, melting point 90-93C
(sintering at 85C).
b) 3-(2-Nitro-5-trifluoromethoxybenzoyl)acetylacetone
was obtained from 8.8 g (35 mmol) of the above 2-nitro-5-
trifluoromethoxybenzoic acid analogously to Example 4c),
13 g of oily crude product.
c) 2-Acetyl-3-hydroxy-6-trifluoro~methoxyquinoline
11.5 g (34.5 mmol) of the above product were introduced
into 105 ml of 20 % strength aqueous potassium hydroxide
solution at 20C, while stirring, and the mixture was
heated under reflux for 30 minutes. After cooling, the pH
was brought to 1 with half-concentrated aqueous HCl, the
precipitate was filtered off with suction and the crude
product (11 g) was chromatographed over silica gel with
n-heptane/ethyl acetate. Corresponding fractions were

2t86717
- 47 -
concentrated and crystallized with petroleum ether;
5.1 g, melting point 87-88C. 0.45 g of the corresponding
N-oxide was obtained as a by-product, melting point 190-
19 1 C .
d) 2-Acetyl-3-benzyloxy-S-trifluoromethoxyquinoline
5.0 g (18.4 mmol) of the above compound were reacted with
2.2 ml (18.4 mmol) of benzyl bromide in diethyl ketone
analogously to Example 4e); 5.6 g of product, melting
point 90-92C (from petroleum ether).
e) 3-Benzyloxy-S-trifluoromethoxyquinoline-2-carboxylic
acid
2.9 g of product were obtained from 2.7 g (7.5 mmol) of
the above compound with l.lS ml (22.5 mmol) of bromine in
sodium hydroxide solution/1,4-dioxane, melting point
286C (with evolution of gas, from the reaction sol-
ution).
f) N-((3-Benzyloxy-S-trifluoromethoxyquinolin-2-yl)-
carbonyl)glycine benzyl ester
1.35 g of product were obtained from 1.8 g (S mmol) of
the above quinoline-2-carboxylic acid, 1.7 g (S mmol) of
glycine benzyl ester tosylate, 2.7 ml ~20 mmol) of NEM,
0.74 g (5.5 mmol) of HOBT and 2.1 g (5 mmol) of CMC
analogously to Example 4 g), melting point 123-124C
(from diisopropyl ether).
g) The title compound was obtained by hydrogenating
1.35 g (2.65 mmol) of the above glycine benzyl ester in
100 ml of tetrahydrofuran with Pd/C (10 %) in a duck-
shaped shaking vessel. After the catalyst had been
filtered off with suction and the filtrate concentrated,
the residue was crystallized with petroleum ether to give
0.7 g of product, melting point 192-194C.

218671 7
- 48 -
Examples 22, 23 and 24 were obtained from corresponding
precursors analogously to Example 21.
Example 22
N-~(6-((Heptafluoropropyl)oxy)-3-hydroxyquinolin-2-
yl)carbonyl)glycine
Example 23
N-((3-Hydroxy-6-(~nonafluorobutyl)oxy)quinolin-2-yl)-
carbonyl)glycine
Example 24
N-((3-Hydroxy-6-((pentafluoroethyl)oxy)quinolin-2-yl)-
carbonyl)glycine
Example 25
N-((6-(3-(Ethyloxy)-1-propyloxy)-3-hydroxyquinolin-2-
yl)carbonyl)glycine
a) 5-(3-Ethyloxy)-1-propyloxy)-2-nitro-benzyl alcohol
5.0 g (~ 30 mmol) of 5-hydroxy-2-nitrobenzyl alcohol were
reacted with 7.1 g (about 40 mmol) of 3-ethoxy-1-propyl
bromide (prepared from 8.3 g (9.2 ml, 80 mmol) of 3-
ethoxy-1-propanol and 15.3 ml (160 mmol) of phosphorus
tribromide in methylene chloride) analogously to Example
4a); 6.1 g of crude product.
b) 5-~3-(Ethyloxy)-1-propyloxy)-2-nitrobenzoic acid
8.1 g of product were obtained from 10.2 g (40 mmol) of
the above alcohol analogously to Example 4b), melting
point 109-111 (from aqueous hydrochloric acid).
c) 3-(5-(3-Ethyloxy-1-propyloxy)-2-nitrobenzoyl)acetyl-
acetone
10.3 g of oily crude product were obtained from 10.2 g
(about 40 mmol) of the above benzoic acid analogously to

- 2186717
- 49 -
Example 4c), after chromatography over silica gel with
n-heptane/ethyl acetate (1:1).
d) 2-Acetyl-6-~3-ethyloxy-1-propyloxy)-3-hydroxy-
quinoline was obtained by reaction of 10 g of the above
compound in 100 ml of 20 % strength aqueous potassium
hydroxide solution (40 minutes, 60C), 2.8 g, melting
point 62-64C ~from n-heptane/ethyl acetate (3:1)).
e) 2-Acetyl-3-benzyloxy-6-~3-ethyloxy-1-propyloxy)-
quino 1 ine
2.8 g (10 mmol) of the above compound were reacted with
1.4 g of potassium carbonate and 1.2 ml ~10 mmol) of
benzyl bromide in 80 ml of diethyl ketone, 3.8 g of oily
product after chromatography over silica gel with
n-heptane/ethyl acetate (1:1).
f) 3-Benzyloxy-6-(3-ethyloxy-1-propyloxy)quinoline-2-
carboxylic acid
3.8 g (10 mmol) of the above acetyl compound were oxi-
dized with aqueous NaOH/bromine/1,4-dioxane (haloform
reaction). 3.0 g of product were obtained, melting point
117-119C (from aqueous hydrochloric acid).
g) N-((3-Benzyloxy-6-(3-ethyloxy-1-propyloxy)quinolin-
2-yl)carbonyl)glycine benzyl ester
2.7 g of oily product were obtained from 2.3 g (6 mmol)
of the above carboxylic acid in 300 ml of anhydrous
methylene chloride with 2.0 g (6 mmol) of glycine benzyl
ester tosylate, 3.3 ml (24 mmol) of NEM, 1.0 g (7.5 mmol)
of HOBT and 2.7 g (6.3 mmol) of CMC analogously to
Examples 4g) and 21f), after chromatography over silica
gel with ethyl acetate.
h) The title compound was obtained by dissolving 2.7 g
of the above dibenzyl compound in 100 ml of tetrahydro-

21867~7
- 50 -
furan and hydrogenating it with Pd/C (10 %) in a duck-
shaped shaking vessel. The catalyst was then filtered off
with suction, the filtrate was concentrated in vacuo and
the residue was crystallized with petroleum ether. 1.3 g
of product were obtained, melting point 133-135C.
Example 26
N-((3-Hydroxy-6-(2-propyloxy)quinolin-2-yl)carbonyl)-
glycine
a) 2-Nitro-5-(2-propyloxy)benzyl alcohol
10 g (60 mmol) of 5-hydroxy-2-nitrobenzyl alcohol were
reacted with 7.0 ml (70 mmol) of isopropyl iodide analog-
ously to Example 4a); after purification over silica gel
with n-heptane/ethyl acetate (3:2), 10.3 g of oily crude
product.
b) 2-Nitro-5-(2-propyloxy)benzoic acid
10.3 g (about 50 mmol) of the above benzyl alcohol were
oxidized analogously to Example 4b); 9.4 g of product,
melting point 131-133C (from methylene chloride).
c) 3-(5-(2-Propyloxy)-2-nitrobenzoyl)acetyl acetone
12.4 g of product were obtained from 9 g (40 mmol) of the
above product (analogously to Example 4c)).
d) 2-Acetyl-3-hydroxy-6-(2-propyloxy)quinoline
12.3 g (40 mmol) of the above product were reacted in
150 ml of 20 % strength aqueous potassium hydroxide
solution at 50C for 45 minutes analogously to Example
4d). Chromatography gave 4.3 g of product, melting point
95-97C (from n-heptane/ethyl acetate (3:1)).

2186717
e) 2-Acetyl-3-benzyloxy-6-(2-propyloxy)quinoline
4.2 g (17 mmol) of the above substance were reacted with
1.4 g ~10 mmol) of potassium carbonate and 2.9 g (2.0 ml,
17 mmol) of benzyl bromide in 100 ml of diethyl ketone,
5.0 g of product, melting point 102-104C (from petroleum
ether).
f) 3-Benzyloxy-6-(2-propyloxy)quinoline-2-carboxylic
acid
3.4 g (10 mmol) of the above acetyl compound, dissolved
in 10 ml of 1,4-dioxane, were added dropwise to a sol-
ution of 4 g of NaOH and 1.6 g (30 mmol) of bromine in
20 ml of water at 0 to 5C. After a thick slurry had
formed, 50 ml of diethyl ether were added, the mixture
was stirred, 1 g of sodium disulfite in 15 ml of water
was then added, the precipitate was filtered off with
suction and dissolved in tetrahydrofuran/water, the
solution was acidified with half-concentrated aqueous
hydrochloric acid, the aqueous phase was extracted with
ethyl acetate and concentrated and the residue was
crystallized with diisopropyl ether. 3.0 g of product
were obtained, melting point 140C (with decomposition).
g) N-((3-Benzyloxy-6-(2-propyloxy)quinolin-2-yl) -
carbonyl)glycine benzyl ester
2.7 g (8 mmol) of the above quinolinecarboxylic acid were
reacted with 2.7 g (8 mmol) of glycine benzyl ester
tosylate, 4.4 ml (32 mmol) of NEM, 1.35 g (10 mmol) of
HOBT and 3.6 g (8.8 mmol) of CMC in 300 ml of anhydrous
methylene chloride at 20C for 24 hours, analogously to
Example 25g). After working up and chromatography over
silica gel with n-heptane/ethyl acetate (3:2), 3.5 g of
oily product were obtained.
h) The title compound was obtained by hydrogenating
3.4 g (7 mmol) of the above dibenzyl compound in 100 ml

2186717
of tetrahydrofuran with Pd/C (10 %) in a duck-shaped
shaking vessel (uptake of 260 ml of hydrogen). The
catalyst was filtered off with suction, the filtrate was
concentrated and the residue was crystallized with
diisopropyl ether. 1.5 g of the colorless title compound
were obtained, melting point 149-151C.
Example 27
N-(~3-Hydroxy-6-phenoxyquinolin-2-yl)carbonyl)glycine
a) 2-Nitro-5-phenoxytoluene
14.1 g (150 mmol) of phenol were dissolved in 120 ml of
anhydrous N,N-dimethylacetamide, while stirring, 20.6 g
~150 mmol) of finely powdered potassium carbonate were
added and the mixture was stirred at 70-80C for
30 minutes. After cooling to 20C, 23.25 g (18.3 ml,
150 mmol) of 5-fluoro-2-nitrotoluene were added dropwise,
the mixture was heated at 135-140C for 2 hours and,
after cooling, concentrated in vacuo, the residue was
introduced into ice and the crystalline product was
filtered off with suction, washed with water and dried,
30 g, melting point 43-46C.
b) 2-Nitro-5-phenoxybenzoic acid
(cf. also Liebigs Ann. 593, 113 (1955))
13 g (56.7 mmol) of the above substance were stirred
under reflux with 85 g of potassium permanganate in
pyridine/water (1:2) for 4 hours. The manganese dioxide
was filtered off hot with suction and rinsed with hot
water, the filtrate was concentrated, the residue was
taken up in 250 ml of saturated aqueous Na bicarbonate
solution, unreacted starting material was filtered off
with suction and the filtrate was brought to pH 1 with
half-concentrated HCl, 4.3 g, melting point 148-150C.
c) 3-(2-Nitro-5-phenoxybenzoyl)acetylacetone

21867~7
- 53 -
12 g of oily crude product were obtained from 15.6 g
(60 mmol) of the above benzoic acid with oxalyl chloride
and magnesium acetylacetonide analogously to Example 4
c) .
d) 2-Acetyl-3-hydroxy-6-phenoxyquinoline
10 g ~29.3 mmol) of the above compound were reacted in
100 ml of 20 % strength aqueous KOH solution analogously
to Example 4 d). After chromatography of the crude
product over silica gel with n-heptane/ethyl acetate
~3:1), 2.5 g of product were obtained, melting point 131-
133C. 0.55 g of the corresponding N-oxide was obtained
as a byproduct, melting point 173-175C.
e) 2-Acetyl-3-benzyloxy-5-phenoxyquinoline
2.5 g (8.9 mmol) of the above compound were reacted with
1.2 g (8.9 mmol) of potassium carbonate and 1.1 ml
~8.9 mmol) of benzyl bromide in 80 ml of diethyl ketone,
3.3 g of product, melting point 116-118C ~from water,
sintering at 100C).
f) 3-Benzyloxy-6-phenoxyquinoline-2-carboxylic acid
2.2 g ~5.96 mmol) of the above compound were subjected to
the haloform reaction analogously to Example 4 f) ~12 ml
of water, 2.6 g of NaOH (60 mmol), 0.9 ml ~18 mmol) of
bromine, 10 ml of dioxane), 2.1 g of product, melting
point 281C-283C.
g) N-~(3-Benzyloxy-6-phenoxyquinolin-2-yl)carbonyl)-
glycine benzyl ester
1.5 g (4 mmol) of the above carboxylic acid were reacted
with 1.35 g (4 mmol) of glycine benzyl ester tosylate,
2.2 ml ~16 mmol) of NEM, 0.67 g (15 mmol) of HOBT and
1.8 g (4.2 mmol) of CMC in 250 ml of anhydrous methylene
chloride analogously to Example 4 g). 1.5 g of product

- 2 1 867 1 7
were obtained, melting point 143-145C (from diisopropyl
ether).
h) The title compound was obtained by hydrogenating
1.5 g of the above glycine ester in tetrahydrofuran with
Pd/C (10 %) in a duck-shaped shaking vessel. 0.7 g of the
title compound was obtained, melting point 225-227C
~from diisopropyl ether).
Example 28
N-~3-Hydroxy-6-(3-methoxyphenoxy)quinolin-2-yl)-
carbonyl)glycine
The title compound was obtained analogously to
Example 27.
a) 5-~3-Methoxyphenyl)oxy)-2-nitrotoluene
35 g of product were obtained from 18 g ~150 mmol) of
3-methoxyphenol and 23.3 g (150 mmol) of 5-fluoro-2-
nitrotoluene, melting point 48-50C (from water).
b) 5-(3-Methoxyphenoxy)-2-nitrobenzoic acid
Melting point 146-151C (from aqueous hydrochloric acid).
c) 3-(5-((3-Methoxyphenyl)oxy)-2-nitrobenzoyl)acetyl-
acetone
oily product after column chromatography.
d) 2-Acetyl-3-hydroxy-6-((3-methoxyphenyl)oxy)quinoline
4.9 g of product were obtained from 7.5 g (20 mmol) of
the above substance after treatment with 75 ml of 20 %
strength ROH (90 minutes, 55C), melting point 102-104C
(from n-heptane/ethyl acetate (3:1)).
e) 2-Acetyl-3-benzyloxy-6-((3-methoxyphenyl)oxy)-
quinoline
oily product after chromatography over silica gel.

2186717
- 55 -
f) 3-Benzyloxy-6-((3-methoxyphenyl)oxy)quinoline-2-
carboxylic acid,
Melting point 142C (with decomposition, from diisopropyl
ether).
g) N-(~3-Benzyloxy-6-((3-methoxyphenyl)oxy)quinolin-2-
yl)carbonyl)glycine benzyl ester
Melting point 118-120C (from petroleum ether).
h) The title compound was obtained analogously to
Example 27 h).
1.1 g of product were obtained from 2 g of the above
substance, melting point 166-167C (from diisopropyl
ether).
Example 29
N-((3-Hydroxy-6-((3-trifluoromethylphenyl)oxy)quinolin-2-
yl)carbonyl)glycine
The title compound was obtained analogously to Example
27.
a) 2-Nitro-5-((3-trifluoromethylphenyl)oxy)toluene
62 g of oily crude product were obtained from 36.5 g
(225 mmol) of 3-hydroxybenzotrifluoride and 27.9 g (225
mmol) of 5-fluoro-2-nitrotoluene.
b) 2-Nitro-5-((3-trifluoromethylphenyl)oxy)benzoic
acid, melting point 153-155C (from aqueous hydrochloric
acid).
c) 3-(2-Nitro-5-((3-trifluoromethylphenyl)oxy)benzoyl)-
acetylacetone
15 g of oily product were obtained from 18 g (55 mmol) of
the above compound after chromatography with n-heptane/
ethyl acetate (4:1).

21~67~
- 56 -
d) 2-Acetyl-3-hydroxy-6-((3-trifluoromethylphenyl)oxy)-
quinoline, melting point 97-99C (from petroleum ether).
e) 2-Acetyl-3-benzyloxy-6-~(3-trifluoromethylphenyl)-
oxy)quinoline,
oily product after chromatography.
f) 3-Benzyloxy-6-~(3-trifluoromethylphenyl)oxy)-
guinoline-2-carboxylic acid
5.7 g (13 mmol) of the above acetyl compound were oxi-
dized analogously to Example 4 f). 5.7 g of product were
obtained from the organic phase without acidification,
melting point 150C (from petroleum ether, foaming).
g) N-((3-Benzyloxy-6-((3-trifluoromethylphenyl)oxy)-
quinolin-2-yl)carbonyl)glycine benzyl ester
5.6 g (12.7 mmol) of the above carboxylic acid were
reacted with glycine benzyl ester tosylate, NEM, HOBT and
CMC analogously to Example 4 g); 3.5 g of product,
melting point 103-105C.
h) The title compound was obtained by hydrogenating
3.4 g of the above benzyl ester in tetrahydrofuran with
Pd/C (10 %) in a duck-shaped shaking vessel. 2.2 g of
product were isolated, melting point 166-168C (from
petroleum ether).
Example 30
N-((7-Chloro-3-hydroxyquinolin-2-yl)carbonyl)glycine
a) 3-(4-Chloro-2-nitrobenzoyl)acetylacetone
45 g of crude product were obtained from 60.5 g (0.3 mol)
of 4-chloro-2-nitrobenzoic acid analogously to Example
4 e)-
b) 2-Acetyl-7-chloro-3-hydroxyquinoline

2 ~ ~6 71 7
18.3 g of product were obtained from 44 g (0.15 mol) of
the above compound analogously to Example 4 d), after
chromatography over silica gel with n-heptane/ethyl
acetate (2:1), melting point 97-99C (from petroleum
5 ether). 2.6 g of the corresponding N-oxide were further-
more obtained, melting point 191C (from diisopropyl
ether).
c) 2-Acetyl-3-benzyloxy-7-chloroquinoline
7.5 g (34 mmol) of the above substance were reacted with
4.7 g (34 mmol) of potassium carbonate and 4.1 ml
(34 mmol) of benzyl bromide in 120 ml of diethyl ketone.
Chromatography over silica gel with n-heptane/ethyl
acetate (4:1) gave 8 g of product, melting point 76-77C
(from petroleum ether).
d) 3-Benzyloxy-7-chloroquinoline-2-carboxylic acid
4.1 g of product were obtained from 4.7 g (15 mmol) of
the above acetyl compound after haloform oxidation (NaOH/
water/bromine/dioxane), melting point 140C (with decom-
position, from water).
e) N-((3-Benzyloxy-7-chloroquinolin-2-yl)carbonyl)-
glycine ethyl ester
3.5 g of product were obtained from 3.2 g (10 mmol) of
the above carboxylic acid, 1.4 g (10 mmol) of glycine
ethyl ester hydrochloride, 3.8 ml (30 mmol) of NEM, 1.5 g
(11 mmol) of HOBT and 4.3 g (10 mmol) of CMC analogously
to Example 4 g), melting point 138-140C (from di-
isopropyl ether).
f) N-((3-Benzyloxy-7-chloroquinolin-2-yl)carbonyl)-
glycine
2.0 g (5.0 mmol) of the above glycine ethyl ester were
hydrolyzed in 150 ml of 1.5 N methanolic NaOH. 1.3 g of

21~67~7
- 58 -
product were obtained, melting point 105-108C (sintering
70C, foaming, from diisopropyl ether).
g) The title compound was obtained by introducing 1.2 g
(3.2 mmol) of the above benzyl compound into 60 ml of
48 % strength aqueous hydrogen bromide and stirring the
mixture at 80C for 45 minutes. After cooling, the
mixture was concentrated in vacuo and the residue was
washed three times with 50 ml of tetrahydrofuran each
time to give 0.57 g of product, melting point 268-270C.
Example 31
N-((7-Chloro-3-hydroxy-6-(2,2,2-trifluoroethyloxy)-
guinolin-2-yl)carbonyl)glycine
a) 4,5-Dichloro-2-nitrotoluene
3,4-Dichlorot~luene was nitrated with concentrated
lS sulfuric acid and fuming nitric acid (d = 1.52).
b) 4-Chloro-2-nitro-5-(2,2,2-trifluoroethyloxy)toluene
40.4 g (360 mmol) of potassium tert-butylate were added
in portions to 60 ml of trifluoroethanol, while stirring
and cooling, and the mixture was heated to 80-90C. After
cooling, 14.4 g (70 mmol) of 4,5-dichloro-2-nitrotoluene
were added and the mixture was stirred at 105C for
1 hour. It was concentrated in vacuo and the residue was
treated with 300 ml of water to give, after filtration
with suction, 12 g of crude product, which were purified
over silica gel with n-heptane/ethyl acetate, 10 g of
product, melting point 76-79C.
c) 4-Chloro-2-nitro-S-(2,2,2-trifluoroethyloxy)benzoic
acid
10 g of the above compound were oxidized in pyridine/
water (1:2) with 85 g of potassium permanganate; 8.2 g of
product, melting point 153-155C (from aqueous hydro-

2 1 ~
- 59 -
chloric acid).
d) 3-(4-Chloro-2-nitro-5-(2,2,2-trifluoroethyloxy)-
benzoyl)acetyl acetone
10.3 g of product were obtained from 10 g (34 mmol) of
the above acid analogously to Example 4c), melting point
138-140C (from petroleum ether).
e) 2-Acetyl-7-chloro-3-hydroxy-6-(2,2,2-trifluoro-
ethyloxy)quinoline
10.2 g (26.6 mmol) of the above compound were reacted in
100 ml of 10 % strength aqueous KOH at 50-70C. After
acidification with half-concentrated HCl, 10 g of crude
product were purified over silica gel with n-heptane/
ethyl acetate (4:1); 4.2 g of product, melting point 104-
105C.
f) 2-Acetyl-3-benzyloxy-7-chloro-6-(2,2,2-trifluoro-
ethyloxy)quinoline
4.2 g (13 mmol) of the above compound were reacted with
1.8 g (13 mmol) of potassium carbonate and 1.6 ml
(13 mmol) of benzyl bromide in 100 ml of diethyl ketone,
4.4 g of product, melting point 110-112C (from water).
g) Sodium 3-benzyloxy-7-chloro-6-(2,2,2-trifluoro-
ethyloxy)quinoline-2-carboxylate
3.3 g (8 mmol) of the above acetyl compound were oxidized
in agueous NaOH/bromine/1,4-dioxane. After addition of
aqueous sodium pyrosulfite (Na2S2O5) solution, the product
which had precipitated out was filtered off with suction
to give 3.6 g of the sodium salt, melting point > 325C.
h) N-((3-Benzyloxy-7-chloro-6-(2,2,2-trifluoro-
ethyloxy)quinolin-2-yl)carbonyl)glycine benzyl ester

2 1 8~7~
- 60 -
3.3 g (8 mmol) of the above carboxylic acid were reacted
with glycine benzyl ester tosylate analogously to Example
4 g); 2.92 g of product, which was reacted further.
i) N-((3-Hydroxy-7-chloro-6-(2,2,2-trifluoroethyloxy)-
quinolin-2-yl)carbonyl)glycine-tetrahydrofuran complex
(0.5 equivalent)
1.12 g (2 mmol) of the above benzyl compound were dis-
solved in tetrahydrofuran and hydrogenated with Pd/C
(10 %) in a duck-shaped shaking vessel. 0.58 g of color-
less product was obtained, melting point 204-206C (from
petroleum ether), which, according to lH-NMR, comprises
0.5 equivalent of tetrahydrofuran.
Example 32
N-((7-Chloro-3-hydroxy-6-(2,2,3,3,3-pentafluoro-
propyloxy)quinolin-2-yl)carbonyl)glycine
Example 33
N-((7-Chloro-6-(2,2,3,3,4,4,4-heptafluorobutyloxy)-3-
hydroxyquinolin-2-yl)carbonyl)glycine
a) 4-Chloro-4-nitro-5-(2,2,3,3,4,4,4-heptafluoro-
butyloxy)toluene was obtained with heptafluorobutanol
analogously to Example 31 b), oily crude product.
b) 4-Chloro-5-(2,2,3,3,4,4,4-heptafluorobutyloxy)-2-
nitrobenzoic acid, analogously to Example 31c), melting
point 115-117C (from petroleum ether).
c) 3-~4-Chloro-5-(2,2,3,3,4,4,4-heptafluorobutyloxy)-2-
nitrobenzoyl)acetylacetone
7.77 g of product were obtained from 7.7 g (19 mmol) of
the above acid analogously to Examples 31 d) and 4 c),
melting point 80-81C (from petroleum ether).
d) 2-Acetyl-7-chloro-6-(2,2,3,3,4,4,4-heptafluoro-

2 1 ~ 6 1 ~ 7
- 61 -
butyloxy)-3-hydroxyquinoline was obtained from 7.7 g of
the above compound analogously to Example 31 e), 2.9 g of
oily product after chromatography over silica gel with
n-heptane/ethyl acetate (4:1).
e) 2-Acetyl-3-benzyloxy-7-chloro-6-(2,2,3,3,4,4,4-
heptafluorobutyloxy)quinoline
3.8 g of oily product were obtained from 2.9 g (6.9 mmol)
of the above compound analogously to Example 31 f).
f) 3-Benzyloxy-7-chloro-6-(2,2,3,3,4,4,4-heptafluoro-
butyloxy)quinoline-2-carboxylic acid
3.4 g of product were obtained from 3.6 g (7 mmol) of the
above acetyl compound analogously to Example 31 g),
melting point 183-185C (from petroleum ether).
g) N-((3-Benzyloxy-7-chloro-6-(2,2,3,3,4,4,4-hepta-
fluorobutyloxy)quinolin-2-yl)carbonyl)glycine benzyl
ester
h) 3.3 g (6.5 mmol) of the above carboxylic acid were
reacted with glycine benzyl ester tosylate analogously to
Example 4 g). After purification of the crude product
over silica gel with n-heptane/ethyl acetate (2:1), 3.3 g
of oily product were obtained.
i) 1.32 g (2 mmol) of the above compound were hydrogen-
ated analogously to Example 31 i); 0.72 g of colorless
product, melting point 172-173C (from petroleum ether).
Example 34
N-((3-Hydroxy-6-(2-propyl)quinolin-2-yl)carbonyl)glycine
Example 35
N-((3-Hydroxy-5-phenoxyquinolin-2-yl)carbonyl)glycine

21 8~ 7
- 62 -
Example 36
N-~(5-~1,3-Dichlorophenoxy)-3-hydroxyquinolin-2-yl)-
carbonyl)glycine
Example 37
N-((5-(1-Butyloxy)-3-hydroxyquinolin-2-yl)carbonyl)-
glycine
Example 38
N-((6-(1-Butyl)-3-hydroxyquinolin-2-yl)carbonyl)glycine
Example 39
N-((6-(1-Hexyl)-3-hydroxyquinolin-2-yl)carbonyl)glycine
Example 40
N-((6-(1-Decyl)-3-hydroxyquinolin-2-yl)carbonyl)glycine
Example 41
N-((3-Hydroxy-6-(1-octyl)quinolin-2-yl)carbonyl)glycine
Example 42
N-((3-Hydroxy-6-phenylquinolin-2-yl)carbonyl)glycine
Example 43
N-((3-Hydroxy-6-(2,2,3,3-tetrafluoropropyloxy)quinolin-2-
yl)carbonyl)glycine
a) 2-Nitro-5-(2,2,3,3-tetrafluoropropyloxy)toluene
28 g of potassium carbonate, 70 ml of tetrafluoropropanol
and 26.4 g of 5-fluoro-2-nitrotoluene were reacted; 45 g
of oily crude product.
b) 2-Nitro-5-(2,2,3,3-tetrafluoropropyloxy)benzoic
acid,
Melting point 140C (with foaming, from aqueous hydro-
chloric acid).
c) 3-(2-Nitro-5-(2,2,3,3-tetrafluoropropyloxy)benzoyl)-
acetylacetone,

2186117
-- 63 --
oily product.
d) 2-Acetyl-3-hydroxy-6-(2,2,3,3-tetrafluoropropyloxy)-
quinoline
13.3 g (35 mmol) of the above substance were stirred in
125 ml of 20 % strength aqueous ROH at 50C for 45
minutes; 7.5 g of product, melting point 119-121C (from
petroleum ether).
e) 2-Acetyl-3-benzyloxy-6-(2,2,3,3-tetrafluoro-
propyloxy)quinoline
Melting point 121-123C (from petroleum ether).
f) 3-Benzyloxy-6-(2,2,3,3-tetrafluoropropyloxy)-
quinoline-2-carboxylic acid
Melting point 123C (with decomposition, from petroleum
ether).
g) N-((3-Benzyloxy-6-(2,2,3,3-tetrafluoropropyloxy)-
quinolin-2-yl)carbonyl)glycine benzyl ester, melting
point 99-101C (from petroleum ether).
h) The title compound was obtained by hydrogenation of
the above benzyl compound, melting point 175-177C (from
petroleum ether).
Example 44
N-((3-Hydroxy-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-
quinolin-2-yl)carbonyl)glycine
a) 2-Nitro-5-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-
toluene prepared from 5-fluoro-2-nitrotoluene and
octafluoro-l-pentanol, oil.
b) 2-Nitro-5-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-
benzoic acid
Nelting point 95-96C (from petroleum ether).

27~G717
- 64 -
c) 3-(2-Nitro-5-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-
benzoyl)acetylacetone
oily product.
d) 2-Acetyl-3-hydroxy-6-(2,2,3,3,4,4,5,5-octafluoro-
pentyloxy)quinoline
Melting point 69-71C (from n-heptane/ethyl acetate
(3:1)).
e) 2-Acetyl-3-benzyloxy-6-(2,2,3,3,4,4,5,5-octafluoro-
pentyloxy)quinoline
f) 3-Benzyloxy-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-
quinoline-2-carboxylic acid, resinous product.
g) N-((3-Benzyloxy-(2,2,3,3,4,4,5,5-octafluoro-
pentyloxy)quinolin-2-yl)carbonyl)-glycine benzyl ester,
oil.
h) The title compound was obtained by hydrogenation,
melting point 170-172C (sintering 115C, from petroleum
ether).
Example 45
N-((6-((3-Chlorophenyl)oxy)-3-hydroxyquinolin-2-yl)-
carbonyl)glycine
Example 46
N-((6-((3-Fluorophenyl)oxy)-3-hydroxyquinolin-2-yl)-
carbonyl)glycine
Example 47
N-((3-Hydroxy-6-(3-(1-propyloxy)phenyloxy)quinolin-2-
yl)carbonyl)glycine
Example 48
N-((6-(3-((Cyclohexylamino)carbonyl)phenyloxy)-3-hydroxy-
quinolin-2-yl)carbonyl)glycine

2 1 867 1 7
- 65 -
Example 49
N-~(6-((4-Chlorophenyl)sulfonyl)-3-hydroxyquinolin-2-
yl)carbonyl)glycine
Example 50
S N-((3-Hydroxy-6-(~4-(2,2,2-trifluoroethyloxy)phenyl)-
sulfonyl)quinolin-2-yl)carbonyl)glycine
Example 51
N-((3-Hydroxy-6-((4-methoxyphenyl)sulfonyl)quinolin-2-
yl)carbonyl)glycine
Example 52
N-((3-Hydroxy-6-((4-(l-propyloxy)phenyl)sulfonyl)-
quinolin-2-ylcarbonyl)glycine
Example 53
N-((6-((4-(1-Butyloxy)phenyl)sulfonyl)-3-hydroxyquinolin-
2-yl)carbonyl)glycine
Example 54
N-((6-((3-Chlorophenyl)sulfonyl)-3-hydroxyquinolin-2-
yl)carbonyl)glycine
Example 55
N-((3-Hydroxy-6-((3-methoxyphenyl)sulfonyl)quinolin-2-
yl)carbonyl)glycine
Example 56
N-((3-Hydroxy-6-((3-trifluoromethylphenyl)sulfonyl)-
quinolin-2-yl)carbonyl)glycine
Example 57
N-((6-((4-Ethyloxyphenyl)sulfonyl)-3-hydroxyquinolin-2-
yl)carbonyl)glycine
Example 58
N-((6-((4-Bromophenyl)sulfonyl)-3-hydroxyquinolin-2-
yl)carbonyl)glycine

21867t7
- 66 -
Example S9
N-((6-(~4-(3-Ethyloxypropyloxy)phenyl)sulfonyl)-3-
hydroxyquinolin-2-yl)carbonyl)glycine
Example 60
N-((6-((2,5-Dichlorophenyl)sulfonyl)-3-hydroxyquinolin-2-
yl)carbonyl)glycine
Example 61
N-((6-((3,4-Dichlorophenyl)sulfonyl)-3-hydroxyquinolin-2-
yl)carbonyl)glycine
Example 62
N-((6-((3,5-Dichlorophenyl)sulfonyl)-3-hydroxyquinolin-2-
yl)carbonyl)glycine
Example 63
N-((6-((3,4-Dir~thoxyphenyl)sulfonyl)-3-hydroxyquinolin-
2-yl)carbonyl)glycine
Example 64
N-((6-((3,5-Bis-trifluoromethylphenyl)sulfonyl)-3-
hydroxyquinolin-2-yl)carbonyl)glycine
Example 65
N-((3-Hydroxy-6-((4-trifluoromethoxyphenyl)sulfonyl)-
quinolin-2-yl)carbonyl)glycine
Example 66
N-((3-Hydroxy-6-((4-trifluoromethylphenyl)sulfonyl)-
quinolin-2-yl)carbonyl)glycine
Example 67
N-((3-Hydroxy-6-((4-(1-propyl)phenyl)sulfonyl)quinolin-2-
yl)carbonyl)glycine
Example 68
N-((-6-((4-(1-Butyl)phenyl)sulfonyl)-3-hydroxyquinolin-2-
yl)carbonyl)glycine

2i~6717
- 67 -
Example 69
N-((3-Hydroxy-6-(1-naphthylsulfonyl)quinolin-2-yl)-
carbonyl)glycine
Example 70
N-((3-Hydroxy-6-~2-naphthylsulfonyl)quinolin-2-yl)-
carbonyl)glycine

Dessin représentatif